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NDT Advance Access published online on September 21, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm393
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Treatment targets in renal fibrosis

Peter Boor1,2, Katarína Sebeková2, Tammo Ostendorf1 and Jürgen Floege1

1Division of Nephrology, RWTH University of Aachen, Aachen, Germany and 2Department of Clinical and Experimental Pharmacotherapy, Slovak Medical University, Bratislava, Slovakia

Correspondence and offprint requests to: Peter Boor, MD, Division of Nephrology, RWTH University of Aachen, Pauwelsstr. 30, 52074 Aachen, Germany. Email: boor{at}email.cz

Keywords: animal models; kidney scarring; progressive renal disease; treatment options



   Introduction
Top
 Introduction
Conclusions
 Acknowledgements
 References
 
Renal fibrosis is the principal process underlying the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). It is a relatively uniform response involving glomerulosclerosis, tubulointerstitial fibrosis and changes in renal vasculature (loss of glomerular and peritubular capillaries) (Figure 1). Of these, tubulointerstitial fibrosis has evolved as the most consistent predictor of an irreversible loss of renal function and progression to ESRD [1].


Figure 1
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  		Fig. 1. Severe tubulointerstitial fibrosis in an experimental rat model of progressive mesangioproliferative glomerulonephritis on day 100 after disease induction. The renal cortical section stained with periodic acid-Schiff (PAS) shows typical tubulointerstitial damage: accumulation of extracellular matrix (*), tubular atrophy (**) and inflammatory infiltrates (***). Glomerular damage is apparent as glomerulosclerosis (arrow) and proteinuria (double arrow). Magnification: 100x.

 
Mechanisms contributing to tubulointerstitial injury and tubular atrophy include glomerular proteinuria, chronic hypoxia, misdirected glomerular ultrafiltration, tubular protein leakage and direct toxic insults of e.g. drugs (reviewed in detail elsewhere [1–6]). Direct or indirect tubulointerstitial injury via oxidative stress and various effector molecules trigger cellular responses like (i) tubular epithelial cell (TEC) apoptosis, (ii) activation of fibroblasts and their phenotypic switch to myofibroblasts, (iii) influx and/or proliferation of lymphocytes/macrophages, fibrocytes (the circulating fibroblast precursors), fibroblasts as well as (iv) epithelial-to-mesenchymal transition (EMT) of TECs.

Renal fibrosis provides an excellent treatment target, since a large variety of pathophysiologically distinct diseases converge finally into this single process. However, we still do not have effective therapies, nor does such a therapy exist in most other types of organ fibrosis. Why? As part of the vital repair process, the regulation and redundancy in this system must be highly effective. The consequence is an amazingly complicated process that involves many cell types and mediators [1,2,4,5,7]. Not unexpectedly, mono-therapeutic approaches, or even a combination of therapies, fail to completely stop the progression of renal fibrosis [8–10]. In addition, not all combination therapies can be additive [11].

When identifying new targets or validating potential therapeutic options, we are confronted with several problems:

  • Rodent models often do not fully mimic the clinical situation. Apart from the obvious species differences, it is often difficult to distinguish whether the tested approach truly affected the phase of interstitial fibrosis or whether it ameliorated the underlying primary renal injury to an extent that halted the progression. This problem is particularly relevant to the present review.
  • Few approaches have been validated in multiple models.
  • In the experimental situation, treatment is rarely started at a time point of established fibrosis (Table 1).
  • Different parameters and techniques are used for the evaluation of fibrosis. Often histological changes are evaluated by semi-quantitative scoring rather than objective quantitative parameters. Standardized consensus approaches are urgently required.
  • Most studies compare intervention to no intervention rather than comparing different approaches amongst each other or in combination with one another.


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  		Table 1. Examples of experimental studies that showed effective antifibrotic treatment aproaches in established secondary renal fibrosis

 
In the following, we will first discuss antifibrotic approaches, that are clinically available or close to being so, and then discuss potential new targets in fibrosis therapy (Table 2).


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  		Table 2. Summary of reviewed targets and/or compounds for treatment of renal fibrotic disease

 
Renin–angiotensin–aldosterone (RAAS) and kallikrein–kinin system
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor type 1 blockers (ARB) are undisputedly the first line drugs in combating renal fibrosis. These drugs, however, are not able to halt the progression completely and in some conditions, like aristocholic acid-induced renal fibrosis in rats, they are not effective at all [12]. Combination therapy of ACEI and ARB [13] or high-dosage of ACEI [14] show potential in experimental studies to arrest or even regress renal fibrosis, at least in the early stages.

Kallikrein cleaves the precursor kininogen to the active vasodilator kinin peptide, bradykinin, which via its B2 receptors mediates protective effects in hypertension, renal injury and fibrosis [15,16]. Gene delivery of kallikrein ameliorated renal scarring without affecting the blood pressure [17], and even reversed established kidney fibrosis [18]. ACE is the same enzyme as kininase II, which degrades active kinins. Thus, ACE inhibition leads to kinin accumulation, which may contribute to the beneficial effects of ACEI.

Aldosterone inhibition, e.g. with mineralocorticoid receptor blockers (spironolacton, eplerenone), also shows beneficial effects in experimental as well as in clinical studies (reviewed in [19,20]).

Renin inhibitors (aliskiren, enalkiren, zalkiren) are promising drugs for combating renal fibrosis as shown in severely hypertensive transgenic rats (dTGR) harbouring the human renin and angiotensinogen gene [21]. Clinical effects on renal fibrosis remain to be determined. The recently discovered receptor for renin and prorenin [(P)RR – (pro)renin receptor] was linked to glomerular fibrosis [22]. (P)RR blockers might be even more potent than renin inhibitors, since renin inhibitors do not block renin or prorenin binding to and activation of (P)RR [22].

Vasopeptidase inhibitors (e.g. AVE7688, omapatrilat) block both ACE and neutral endopeptidase, which results in a more pronounced blood pressure decrease, as compared with ACEI. AVE7688 potently retarded renal fibrosis in an animal model of Alport syndrome [23]. However, the higher incidence of angioedema with omapatrilat as compared with ACEI has limited clinical studies thus far.

Endothelin, sympathic nerve system
Endothelin, acting via its receptors ETA and ETB, is a potent vasoconstrictor and mediator of fibrotic response [2,24–26]. Although the dual inhibitor of ETA and ETB bosentan is in clinical use, its benefits vs side effects (mainly hepatotoxicity and fluid retention) in CKD patients remain largely to be evaluated.

Blockade of sympathic nerve activity with moxonidine reduced the progression of fibrosis in 5/6-nephrectomized rats without affecting blood pressure [27,28]. Selective {alpha} and ß blockers in subantihypertensive dosages also ameliorated the development of renal fibrosis [29,30]. In cyclosporine-induced renal damage, however, kidney denervation had no effect on the development of fibrosis [31].

Environmental factors and metabolic syndrome
Smoking accelerates progression of kidney diseases, in part through blood pressure-mediated effects [32], but at least in experimental situations, also via a possible profibrotic effect [33,34]. Another independent factor that leads to progression of kidney disease is obesity [36]. Various pathways, including increased metabolic demands on the kidney, hyperinsulinaemia or leptin overproduction, were shown to induce or promote kidney scarring in obesity [37–40]. Diet-induced hypercholesterolaemia in rodents or pigs resulted in renal fibrosis, which was reversible by lipid-lowering dietary interventions [41,42]. Several experimental studies demonstrated the protective effect of statins on kidney scarring, which may relate to their lipid-lowering but also to their anti-inflammatory actions [43–45]. First clinical data confirmed the renoprotective effects of statins [46] and large trials in CKD patients are underway.

Immunosuppressive agents
Mycophenolate mofetil (MMF) ameliorated fibrosis in various experimental models [47–50]. These effects were comparable, but not additive, with those of enalapril or lisinopril [48,49]. Confirmatory data in transplanted patients has recently emerged [51]. Rapamycin attenuated renal fibrosis in patients with kidney transplantation [52] and in unilateral ureteral obstruction (UUO) in rats [53]. Dexamethasone reduced fibrosis in renin transgenic rats similiarly to MMF [55], but failed to reduce fibrosis in mercuric chloride-treated rats, whereas tacrolimus was effective in the latter [56].

Turnover and composition of the extracellular matrix
Matrix metalloproteinases (MMPs) were initially thought to be beneficial in renal fibrosis, given that they degrade extracellular matrix (ECM) proteins. Recent data suggest that their role in renal scarring may be much more complex [57] (Figure 2). In renal fibrosis, local delivery of MMP-1 reduced collagen content in streptozotocin-induced diabetic nephropathy in rats [58]. On the other hand, tubular MMP-2 overexpression in mice induced renal fibrosis [59] and selective pharmacological MMP-2 inhibition increased fibrosis in UUO [60].


Figure 2
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  		Fig. 2. Complexity of MMP driven proteolysis. Each of the 23 human and 24 murine MMPs can be regulated at different levels, ranging from RNA processing to activation of inactive MMPs (zymogens) and/or degradation of active MMPs by other proteases (e.g. other MMPs). The broad range of the MMPs targets resulting in a diversity of biological functions adds another level of complexity to this protease system. With respect to fibrosis, it seems obvious, that MMPs should not be viewed as merely ECM degrading ‘anti-fibrotic’ molecules. Adapted and modified from [285]. ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; FGF, fibroblast growth factor; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; TGF-ß, transforming growth factor-ß; TIMP, tissue inhibitor of MMPs; TNF-{alpha}, tumour necrosis factor-{alpha}; VEGF, vascular endothelial growth factor.

 
Tissue inhibitors of matrix metalloproteinases (TIMP-1 to -4) are natural MMP inhibitors. Genetic TIMP-1 deletion in mice had no influence on experimental kidney fibrosis [61,62], whereas overexpression of TIMP-1 increased age-related fibrosis [63].

Membrane-bound ‘a disintegrin and metalloprotease domain’ proteases (ADAMS) and secreted ‘ADAM with thrombospondin motifs’ proteases (ADAMTS) are two other important families of proteases (containing more than 50 members). ADAM-19 is abundant in fibrotic renal lesions in human biopsies [64]. ADAMTS-1-deficient mice exhibited kidney fibrosis in addition to renal malformations [65].

Some proteases of the fibrinolytic pathway, i.e. plasminogen activator inhibitor-1 (PAI-1) [66–69], tissue-type plasminogen activator (tPA) [70,71] and plasminogen [72,73] are important profibrotic factors. However, in anti-glomerular basement membrane (anti-GBM) nephritis, all three factors proved to be antifibrotic, which may relate to their involvement in the glomerular coagulation cascade, i.e. effects on the primary renal disease as opposed to direct effects on renal fibrosis [68,74,75]. Genetic urokinase-type plasminogen activator (uPA) deficiency had no effect on fibrosis in UUO or anti-GBM nephritis; deficiency of its receptor (uPAR) was antifibrotic in UUO but not in anti-GBM nephritis [66].

Tissue transglutaminase (Tg) stabilizes ECM by protein cross-linking. This leads, for example, to resistance of such modified collagens to proteolytic degradation by MMPs. Tissue Tg is upregulated and correlates closely with the severity of renal fibrosis in experimental models and in humans [76,77]. At least in vitro, inhibition of tissue TG reduced glucose-induced deposition of ECM proteins in renal proximal tubular epithelial cells [77].

Oral administration of a protease mixture (trypsin and bromelain with rutosid added as an antioxidant) reduced renal fibrosis in rats with 5/6-nephrectomy or Goldblatt hypertension independently of blood pressure [78,79]. Single proteases or their mixtures are used in human medicine.

Relaxin is a small peptide hormone with potent antifibrotic activity in the kidney [80–82]. Its benefit may derive in part from interference with transforming growth factor-ß (TGF-ß), a potent profibrotic cytokine [83]. Continuous subcutaneous infusion of relaxin showed promising results in a phase II clinical trial in patients with systemic sclerosis, but this effect was not confirmed in a phase III trial [84].

Pirfenidone is a potent inhibitor of ECM accumulation as shown in several experimental models of renal damage, e.g. mesangioproliferative GN, 5/6-nephrectomy or UUO [85,86], and in patients with idiopathic pulmonary fibrosis and advanced liver fibrosis. We lack clinical data in renal patients.

Integrins are heterodimeric cell receptors for the ECM. Integrin {alpha}1 chain-deficient mice developed more severe glomerulosclerosis in adriamycin-induced renal injury [87]. In contrast, genetic {alpha}1 chain-deficiency or antagonism of {alpha}1 chain reduced fibrosis in a mouse model of Alport syndrome [88] and in rats with crescentic GN [89] or mesangioproliferative GN [90]. Integrin {alpha}Vß6 binds to and activates latent TGF-ß. Mice deficient of the ß6 integrin chain exhibited reduced fibrosis following UUO [91]. Deficiency of ß6 or {alpha}Vß6-blocking antibodies also reduced fibrosis in Alport mice [92]. In contrast, genetic deficiency of the {alpha}8-chain did not contribute to glomerulosclerosis or fibrosis [93]. Outside-in signalling of integrins involves, amongst other functions, activation of the integrin-linked kinase (ILK) pathway. ILK was suggested to participate in the development of renal fibrosis [94,95].

Collectively these data suggest that some systems, such as MMPs, the fibrinolytic pathway and integrins, may be difficult to interfere with clinically, given their complex nature, their redundancy and their sometimes opposing biological effects. However, some attractive therapeutic options such as Tg- antagonists are starting to emerge.

Complement system
The terminal complex of complement, C5b-9 (or membrane attack complex—MAC) is formed at sites of tubulointerstitial injury [1], its depletion in experimental nephropathy reduces proteinuria [96] and inhibition of MAC formation in proteinuric animal models ameliorated tubulointerstitial injury [1,97–99]. However, genetic C6 deficiency, which precludes MAC formation, did not affect the severity of non-proteinuric models of tubulointerstitial injury [100], suggesting that MAC mediates tubulointerstitial damage in proteinuric renal diseases only [100].

Besides C5b-9, complement C5 and in particular C5a may also become a target in renal fibrosis: in experimental murine immune-complex GN, genetic deficiency of the C5a receptor (C5aR) led to reduced interstitial cell infiltration and tubulointerstitial damage without affecting the glomerular injury. This pointed to a role of the anaphylatoxin C5a, a small peptide released from C5, in tubulointerstitial injury [105]. In the mouse UUO model, genetic C5 deficiency or pharmacological inhibition of C5aR potently reduced tubulointerstitial fibrosis [106]. C5aR deficiency or antagonism also attenuated the course of lupus nephritis in mice [107,108]. C5aR antagonists and anti-C5 antibodies (eculizumab) were/are being evaluated in clinical trials.

Complement regulatory proteins such as Crry, which inhibits C3 activation, or CD59, which inhibits C5b-9 formation, may also be of interest: Local deficiency of Crry aggravated tubular damage and fibrosis in puromycin-induced nephropathy (PAN) and in models of renal transplantation [101,102]. Crry and CD59 were equally therapeutic in PAN [103]. Treatment with Crry also decreased renal ECM accumulation in murine lupus nephritis [104], but here, effects on the immune system vs direct, antifibrotic effects are difficult to distinguish.

Cytokines
Few data are available on the role of interleukins (IL) in renal fibrosis. One exception is IL-1ß, whose profibrotic properties in experimental renal disease have been established [109–113]. Although an IL-1 receptor antagonist (anakinra) is already in clinical use, it has not been tested so far in patients with renal fibrosis. In mice lacking the IL-8 receptor, which mediates transepithelial migration, trapped neutrophils lead to tissue destruction and renal fibrosis after experimental pyelonephritis [114]. An antifibrotic action of IL-10 was described in 5/6-nephrectomized rats [115]. IL-10 is also anti-inflammatory and anti-atherogenic and systemic treatment was well tolerated in psoriasis patients [116]. However, systemic treatment with IL-10 was ineffective in patients with rheumatoid arthritis or Crohn's disease [116], unless locally delivered in the gut of Crohn's patients. Thus, local delivery in renal patients could become a limiting factor. It also should be stressed that in systemic lupus erythematosus IL-10 seems to be a harmful factor [116]. Early IL-4 administration in rats with crescentic GN diminished tubulointerstitial fibrosis in the later course of the disease [117]. Although IL-5, -6 and -13 are involved in the pathogenesis of some renal diseases, no data currently exist on their role in renal scarring.

Interferon-{gamma} (IFN-{gamma}) has antifibrotic properties in vitro [118] and administration to 5/6-nephrectomized rats decreased kidney fibrosis [119]. However, in rats with mesangiopoliferative GN, IFN-{gamma} treatment decreased mesangial cell proliferation but not glomerular ECM accumulation [120]. IFN-{alpha} reduced interstitial fibrosis in carbon tetrachloride-induced nephrotoxicity [121]. Although IFN treatment long-term clinical therapy is feasible, the case for such treatment in renal fibrosis patients is not particularly strong.

Tumour necrosis factor-{alpha} (TNF-{alpha}) is a well-recognized promoter of fibrosis in the kidney [122–124]. Although anti-TNF-{alpha} antibodies are highly effective in patients with rheumatoid arthritis, side effects such as serious infections and malignancies [125], or increased mortality in patients with chronic heart failure [126], may limit clinical trials in renal fibrosis.

Chemokines
Several chemokines and their receptors were shown to act in a profibrotic manner, mainly via recruitment of inflammatory cells into the tubulointerstitium [6]. These profibrotic molecules include monocyte chemoatractant protein-1 (MCP-1/CCL2) and its receptor CCR2 [127–133], RANTES (CCL5) and its receptor CCR1 (but not CCR5) [134–137], macrophage-colony stimulating factor (M-CSF) [138], osteopontin [139–141] and fractalkine receptor 1 (CX3CR1) [142]. The secondary lymphoid tissue chemokine (SLC/CCL21) and its receptor CCR7 have been implicated in the regulation of fibrocyte infiltration of the renal interstitium and promotion of fibrosis [143]. Several problems render a translation of these results into clinical trials difficult [6]: (i) There are considerable species differences in the expression of chemokines and their receptors. (ii) Although profibrotic in most disease models, chemokines might be also beneficial; e.g. lack of CCR1 or CCR2 was antifibrotic in UUO but aggravated renal injury in crescentic GN [144,145]. (iii) Chemokine receptor antagonists developed for clinical use, e.g. antagonists of CCR2 and CCR5, cross-react with other closely related G-protein-coupled receptors, resulting in insufficient specificity in humans. An alternative approach could be the inhibition of chemokine signalling via phosphatidylinositol-3-kinase-{gamma} (PI3K{gamma}). Indeed, a PI3K{gamma} inhibitor ameliorated the severity of lupus nephritis in mice [146].

TGF-ß, TGF-ß signalling molecules, p38 MAPK, bone morphogenic protein-7 (BMP-7)
TGF-ß, a central mediator of fibrosis, exerts its biological, in particular immunological, functions via complex signalling pathways [147]. In view of its potent action as an endogenous immunosuppressant, complete blockade of TGF-ß signalling could have serious adverse consequences. Thus, TGF-ß-deficient mice die of a multifocal inflammatory syndrome [148]. However, the complexity of TGF-ß regulation and its downstream pathways provide possibilities for more specific treatment targets (e.g. BMP-7, HGF, CTGF, Smads) (Figure 3). It should be mentioned that while most of the research focuses on the TGF-ß1 isoform, the other isoforms, ß2 and ß3, also have profibrotic effects on kidney cells [149].


Figure 3
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  		Fig. 3. TGF-ß signalling and it modulation. The simplified scheme shows Smad signalling of TGF-ß and BMP-7 and mainly encompasses molecules discussed in the text. Different molecules modify extracellularly the activity of TGF-ß or BMP-7 (note: CTGF effects on BMP-4 have been shown, but its effects on BMP-7 signalling are less clear). TGF-ß or BMP-7 binding to their receptors induces heteromeric receptor complexes with kinase activation (ALK5 and ALK3, respectively) that leads to recruitment and phosphorylation of Smads (Smad2/3 and Smad1/5, respectively). These phospho-Smads (pSmad) form heteromers with Smad4 and are transported to the nucleus where they regulate gene expression. Antagonistic effects of BMP-7 on TGF-ß signalling are depicted in the example of collagen type I expression and on nuclear shuttling and phosphorylation of Smad3. Non-Smad TGF-ß signalling, shown in the right side of the picture, can involve activation of p38 MAPK, JNK and Rho. The modulation of TGF-ß-induced gene transcription by Smad co-repressors Ski and SnoN in nucleus is also shown. Arrows indicate stimulatory effects and blunted lines inhibitory effects. ‘P’ stands for phosphorylation. ALK3, BMPR-IA kinase; ALK5, TßRI kinase; BMP-7, bone morphogenic protein-7; BMPR-IA, BMP receptor IA; BMP-RII, BMP receptor II; JNK, c-Jun amino-terminal kinase; KCP, kielin/chordin-like protein; p38 MAPK, p38 mitogen-activated protein kinase; TßR, TGF-ß1 receptor; TGF-ß, transforming growth factor-ß; USAG-1, uterine sensitization-associated gene 1.

 
Overexpression of Smad7, an inhibitory factor in the TGF-ß signalling pathway, reduced renal fibrosis in 5/6-nephrectomy and UUO [150–152]. Alternatively, genetic deletion of the agonistic signalling molecule, Smad3, protected kidneys from interstitial fibrosis [153,154]. The plant alkaloid halofuginone is an inhibitor of collagen I synthesis, recently shown to also inhibit Smad3 [155]. Halofuginone was successfully used for topical treatment of fibrosis in patients with scleroderma, had good tolerability after oral administration and is currently being tested in cancer patients. Snail is a transcription factor involved in EMT and is strongly activated by TGF-ß. Activation of Snail in adult transgenic mice induced renal fibrosis and Snail was found to be overexpressed in human fibrotic kidney [156]. Other targets in renal scarring might be the antifibrotic Smad co-repressors, Ski and SnoN [157,158]. Inhibition of the TGF-ß1 receptor kinase (ALK5) alone [159,160] or in combination with inhibition of p38 mitogen-activated protein kinase (MAPK) [161] ameliorated renal fibrosis. Inhibition of p38 MAPK also reduced fibrosis in UUO and unilateral kidney ischaemia–reperfusion [162,163], and p38 MAPK inhibitors are currently tested in clinical trials in patients with inflammatory diseases, e.g. asthma. Lack of decorin, a proteoglycan involved in ECM assembly and a TGF-ß antagonist, elevated interstitial fibrosis in UUO [164] and delivery of decorin by gene therapy prevented fibrosis in glomerulonephritic rats [165].

BMP-7 was shown to reduce (more potently than enalapril) or even reverse renal interstitial fibrosis in various experimental models [166–170]. Furthermore, treatment with BMP-7 had beneficial effects on renal osteodystrophy and reduced vascular calcification in uraemia [171,172]. However, in the protein overload model in rats, treatment with BMP-7 protein showed no significant effects on renal fibrosis [173]. BMP-7 therapy in patients has not yet been reported but the results of ongoing studies are eagerly awaited. Kielin/chordin-like protein (KCP) and uterine sensitization-associated gene-1 (USAG-1) are an endogenous BMP-7 agonist and antagonist, respectively. Mice lacking KCP were more susceptible to development of renal fibrosis [174], whereas mice lacking USAG-1 were protected [175].

Hepatocyte growth factor (HGF) and connective tissue growth factor (CTGF; CCN2)
HGF was shown to have antifibrotic properties in different animal models via inhibitory effects on Smad2/3 and activation of SnoN, which binds and inactivates Smad2 [176–179]. However, HGF overexpression or its glomerular ultrafiltration in diabetic nephropathy rats with proteinuria have also been implicated in the development of renal fibrosis [180,181]. The pro-carcinogenic HGF effects [182] raise safety concerns for clinical trials.

CTGF, a potent profibrotic molecule, is at least in part a direct downstream mediator of TGF-ß. It decreases vascular endothelial growth factor (VEGF) signalling, enhances signalling of several growth factors [e.g. TGF-ß itself, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF)] and directly regulates cell functions (adhesion, migration, proliferation) via binding to integrins and ECM [183,184]. CTGF is a direct mediator of profibrotic effects of AGEs, is up-regulated in humans with renal fibrosis and its inhibition resulted in a potent reduction of fibrosis in experimental diabetic nephropathy, UUO and 5/6-nephrectomy [183–188]. Anti-CTGF therapy is now in clinical trials in diabetic nephropathy.

Vascular endothelial growth factor (VEGF)
VEGF is a potent angiogenic factor, which is also involved in fibrosis [189]. In rats with 5/6-nephrectomy, cyclosporine nephropathy and thrombotic microangiopathy, administration of VEGF121 reduced fibrosis and renal damage [189–191]. Consistent with this, VEGF antagonism accelerated renal damage in mice with progressive crescentic GN [192] and in rats with mesangioproliferative GN [193]. However, the action of VEGF may depend on the biological context, since, in contrast to the above data, a VEGF neutralizing antibody ameliorated early renal injury, in particular glomerular hypertrophy, in 5/6-nephrectomized rats, in mice fed with a high-protein diet and in rats with diabetic nephropathy [194–197]. Various anti-VEGF aproaches are approved for use in patients, and renal side effects include proteinuria and hypertension [198]. Given the above data, the complexity of the VEGF system (five family members with alternative splicing, four different receptors) and potential adverse pro-angiogenic effects of VEGF-therapy, it appears uncertain whether VEGF administration or blockade will become a useful approach in patients with renal fibrosis.

Platelet-derived growth factor (PDGF)
PDGF is a key mediator of fibrosis in different organs, including the kidney (Table 3 and Figure 4). The PDGF–B and –D isoforms mediate glomerular ECM accumulation in GN [199]. Their main receptor, i.e. PDGFR-ß (Figure 4), is upregulated in the fibrotic tubulointerstitium [199]. PDGF-B also exerts its profibrotic effects in the tubulointerstitial compartment [200,201]. PDGF-D expression increases in obstructive uropathy in both humans and mice [202]. In rats with progressive mesangioproliferative GN, treatment with PDGF-D-neutralizing antibody ameliorated the early glomerular damage and the subsequent tubulointerstitial fibrosis [203]. Furthermore, this treatment prevented progression and fibrosis, even if initiated at the stage of established tubulointerstitial damage [204]. In a phase I clinical trial, a PDGF-D-neutralizing antibody had promising safety/tolerability profile, pharmacodynamic properties and long half-life (Hahne et al., J Am Soc Nephrol 2005; 16: Abstract SA-PO1017).


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  		Table 3. Experimental in vivo modulation of PDGF signalling in renal fibrosis

 

Figure 4
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  		Fig. 4. Simplified scheme of PDGF signalling and its regulation. Only the main molecules relevant for this review are listed. PDGF -AA, -AB and -BB are secreted in an active form whereas PDGF -DD and -CC are activated extracellularly via proteolytic cleavage of CUB-domain by urokinase plasminogen activator (tPA) or tissue plasminogen activator (uPA), respectively. Binding of PDGF isoforms results in autophosphorylation of the appropriate PDGF receptor. This subsequently leads to recruitment and activation of downstream signalling pathways such as Jak/STAT, PI3K, PLC-{gamma} or MAPK, which via regulation of gene expression mediate the biological functions of PDGF isoforms, e.g. proliferation, chemotaxis, migration or ECM production. The signalling pathways depicted are common to all three PDGF receptors and the signal transduction results in overlapping yet distinct biological effects depending on the receptor and cell type (e.g. via different binding affinities of the signalling molecules to phosphorylated receptors). An example of a relevant profibrotic cross-talk is the cooperation of PDGF and integrin signalling. Binding of ECM components (e.g. fibronectin, laminin) to integrins activates outside-in signalling via the focal adhesion kinase (FAK) pathway that enhances PDGF induced MAPK signalling. This results in enhanced cell proliferation and migration. Integrins also cooperate with other receptors for growth factors and directly activate signalling pathways such as PI3K, JNK and ILK. Various other regulatory steps might be involved in PDGF-signalling in fibrosis, e.g. regulation of PDGF and PDGFR expression, PDGF degradation or binding to non-signalling molecules (e.g. SPARC or heparin-sulphate proteoglycans). ECM, extracellular matrix; FAK, focal adhesion kinase; ILK, integrin linked kinase; JAK, Janus kinases; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphatidyl-inositol-3-kinase; PLC-{gamma}, phospholipase C-{gamma}; STAT, Signal transducers and activators of transcription; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator.

 
The PDGFR-{alpha} ligand PDGF-C (Figure 4), also seems to be an important mediator of fibrogenic stimuli. PDGF-C is expressed de novo in the fibrotic interstitium of rat and human kidneys [205,206] and its specific antagonism in the mouse UUO reduced fibrotic changes (Eitner et al., submitted for publication).

Imatinib (STI-571) is widely used in cancer therapy as a multi-kinase blocker of the c-abl, c-kit and PDGFR tyrosine kinases. Imatinib ameliorated renal fibrosis in UUO [207] and retarded the development of experimental diabetic [208] and chronic allograft nephropathy [209]. It remains uncertain whether this beneficial effect of imatinib was indeed mediated via reduction of PDGF signalling or whether it related to effects on c-abl kinase [207]. In clinical studies, side effects of imatinib include effects on haematopoesis, heart [210] and bone [211].

Other growth factors
The role of basic fibroblast growth factor-2 (FGF-2) in renal fibrosis is well established, at least in vitro [212–214]. FGF-1 and its receptor were also identified in human interstitial fibrotic lesions [215]. Specific interventions have not been performed in either case in renal fibrosis.

Inhibition of epidermal growth factor receptor (EGFR) is protective against the development of fibrosis in models of hypertensive renal damage and renal mass reduction [216,217]. Expression of a dominant negative EGFR prevented renal lesions induced by chronic Ang II infusion [218].

Similarly protective in the above model were the genetical deletion of TGF-{alpha} or pharmacological inhibition of its activating sheddase TACE (ADAM17) [218]. Anti-EGFR treatment is approved for treatment of some cancers.

Nitric oxide, NF-{kappa}B and Rho/Rho kinase
Enhanced production of nitric oxide (NO) following L-arginine administration prevented progression of renal fibrosis in several models [219–221] but accelerated it in mice with lupus nephritis [222] and adriamycin nephropathy [223]. In two different models of non-immune progressive kidney damage, pharmacological inhibitors of inducible NO synthase (NOS) [223] or endothelial NOS [224] reduced renal fibrosis. Studies in the UUO model using iNOS-deficient mice or using liposome-mediated iNOS gene transfer confirmed the protective role of iNOS [225,226], and genetic eNOS deficiency in mice led to progressive focal kidney scarring [227]. A second messenger of NO, cGMP, is synthesized by soluble guanylate cyclase (sGC) and degraded by phosphodiesterases (PDE). Stimulation of sGC slowed fibrosis development in progressive mesangioproliferative GN [228]. The PDE-5 inhibitor, sildenafil, effectively prevented the developmet of fibrosis, but it was ineffective in reversing established lesions [229]. Another PDE inhibitor, pentoxifiline, was antifibrotic in UUO and, combined with an ACEI, after 5/6 nephrectomy [230,231], but was less effective in a head-to-head comparison with a compound stimulating sGC [231]. In UUO, however, neither PDE-4 inhibition nor an A2A adenosine receptor agonist were able to reduce kidney damage [232].

Nuclear factor-{kappa}B (NF-{kappa}B) activation is a central convergence point of many proinflammatory pathways and a downstream effector of profibrotic molecules such as AGEs, the RAAS system or Smad7 [233]. Reduced renal fibrosis was noted following inhibition of NF-{kappa}B, e.g. with curcumin (diferuloylmethane) [233,234]. First clinical trials with curcumin in patients with malignancies showed no dose-dependent toxicity and phase II trials are underway.

Signalling via the G protein Rho and its associated Rho-kinase (ROCK) has been linked with renal fibrosis using two Rho-kinase inhibitors, Y-27632 and fasudil [235–238]. Both were already successfully used in clinical trials in patients with cardiovascular diseases [239]. Nevertheless, genetic deletion of ROCK1 had no effect on renal fibrosis in UUO [240]. The involvement of Rho/ROCK in human renal disease is largely unkown.

Stem cells
Stem cells hold great promise in acute renal failure and possibly even in chronic, fibrosing renal failure [241]. Indeed, three recent studies showed a beneficial effect of bone marrow-derived cells in a mice model of Alport syndrome [242–244]. However, very few studies have so far addressed the latter situation, and the challenge is to prevent stem cells receiving profibrotic signals from their environment and/or to prevent their maldifferentiation. Thus, it has recently been shown that bone marrow-derived myofibroblasts will contribute to renal fibrosis following ischaemia reperfusion injury [245]; and we observed that administration of mesenchymal stem cells to rats with progressive mesangioproliferative GN initially improved acute renal failure, but in the long-term, these cells adopted an adipocyte-like phenotype in glomeruli and induced an intense fibrotic response [246].

Other treatment targets and approaches
There is a number of targets that might be potentially effective in treatment of renal fibrosis (Table 2). Some of them were already tested in several experimental and/or small clinical studies, e.g. tranilast, 1,25 dihydroxyvitamin D, erythropoietin or glitazones, whereas others are single-study reports or descriptive studies without functional links to renal fibrosis (Table 2).



   Conclusions
Top
 Introduction
 Conclusions
Acknowledgements
 References
 
In the past years, many promising targets for the treatment of renal fibrosis have been validated in various animal models, and even more new targets have been identified. For several of the targets reviewed, substances/drugs have already been developed, are being tested, or are already being therapeutically employed in patients with non-renal indications. Renal fibrosis, in contrast, remains a largely uncharted territory in clinical trials. The reasons for this are certainly multifactorial and may include long study durations if hard endpoints, i.e. loss of GFR, are to be aimed for and, in particular, the lack of non-invasive markers or diagnostic tools to assess kidney scarring, and thus, monitor therapy. However, the industry has noted the enormous potential market, given the possibility of developing antifibrotic therapy that might be of benefit in many different types of organ fibrosis. Furthermore, there is hope that with a large consortia search for biomarkers and advancing ultrasound, or through MR-based or molecular-imaging techniques, even monitoring of the disease process may become feasible in the near future.



   Acknowledgements
Top
 Introduction
 Conclusions
 Acknowledgements
References
 
We apologize to all authors whose important work we could not cite due to space limitations. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) OS 196/1-1 (T.O.) and SFB 542, project C7 (T.O., J.F.).

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Conclusions
 Acknowledgements
 References
 

  1. Nangaku M. Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern Med (2004) 43:9–17.[CrossRef][Web of Science][Medline]
  2. Chatziantoniou C, Dussaule JC. Insights into the mechanisms of renal fibrosis: is it possible to achieve regression? Am J Physiol Renal Physiol (2005) 289:F227–F234.[Abstract/Free Full Text]
  3. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol (2000) 15:290–301.[CrossRef][Web of Science][Medline]
  4. Iwano M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens (2004) 13:279–284.[Web of Science][Medline]
  5. Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int (2006) 69:213–217.[CrossRef][Web of Science][Medline]
  6. Sean EK, Cockwell P. Macrophages and progressive tubulointerstitial disease. Kidney Int (2005) 68:437–455.[CrossRef][Web of Science][Medline]
  7. Eitner F, Floege J. Novel insights into renal fibrosis. Curr Opin Nephrol Hypertens (2003) 12:227–232.[CrossRef][Web of Science][Medline]
  8. Kondo S, Shimizu M, Urushihara M, et al. Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat. J Am Soc Nephrol (2006) 17:783–794.[Abstract/Free Full Text]
  9. Yu L, Border WA, Anderson I, McCourt M, Huang Y, Noble NA. Combining TGF-beta inhibition and angiotensin II blockade results in enhanced antifibrotic effect. Kidney Int (2004) 66:1774–1784.[CrossRef][Web of Science][Medline]
  10. Yang J, Dai C, Liu Y. Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol (2002) 13:2464–2477.[Abstract/Free Full Text]
  11. El Chaar M, Chen J, Seshan SV, et al. The effect of combination therapy with enalapril and the TGF-{beta} antagonist 1D11 in unilateral ureteral obstruction. Am J Physiol Renal Physiol (2007) 292:F1291–F1301.[Abstract/Free Full Text]
  12. Debelle FD, Nortier JL, Husson CP, et al. The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids. Kidney Int (2004) 66:1815–1825.[CrossRef][Web of Science][Medline]
  13. Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int (2005) 67:799–812.[CrossRef][Web of Science][Medline]
  14. Adamczak M, Gross ML, Krtil J, et al. Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol (2003) 14:2833–2842.[Abstract/Free Full Text]
  15. Bledsoe G, Crickman S, Mao J, et al. Kallikrein/kinin protects against gentamicin-induced nephrotoxicity by inhibition of inflammation and apoptosis. Nephrol Dial Transplant (2006) 21:624–633.[Abstract/Free Full Text]
  16. Schanstra JP, Neau E, Drogoz P, et al. In vivo bradykinin B2 receptor activation reduces renal fibrosis. J Clin Invest (2002) 110:371–379.[CrossRef][Web of Science][Medline]
  17. Chao J, Bledsoe G, Yin H, Chao L. The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction. Biol Chem (2006) 387:665–675.[CrossRef][Web of Science][Medline]
  18. Bledsoe G, Shen B, Yao Y, Zhang JJ, Chao L, Chao J. Reversal of renal fibrosis, inflammation, and glomerular hypertrophy by kallikrein gene delivery. Hum Gene Ther (2006) 17:545–555.[CrossRef][Web of Science][Medline]
  19. Hostetter TH, Ibrahim HN. Aldosterone in chronic kidney and cardiac disease. J Am Soc Nephrol (2003) 14:2395–2401.[Abstract/Free Full Text]
  20. Hollenberg NK. Aldosterone in the development and progression of renal injury. Kidney Int (2004) 66:1–9.[CrossRef][Web of Science][Medline]
  21. Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension (2005) 46:569–576.[Abstract/Free Full Text]
  22. Nguyen G. The (pro)renin receptor: pathophysiological roles in cardiovascular and renal pathology. Curr Opin Nephrol Hypertens (2007) 16:129–133.[Web of Science][Medline]
  23. Gross O, Koepke ML, Beirowski B, Schulze-Lohoff E, Segerer S, Weber M. Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688. Kidney Int (2005) 68:456–463.[CrossRef][Web of Science][Medline]
  24. Hocher B, Paul M. Transgenic animal models for the analysis of the renal endothelin system. Nephrol Dial Transplant (2000) 15:935–937.[Free Full Text]
  25. Neuhofer W, Pittrow D. Role of endothelin and endothelin receptor antagonists in renal disease. Eur J Clin Invest (2006) 36 [Suppl 3]:78–88.
  26. Pfab T, Thone-Reineke C, Theilig F, et al. Diabetic endothelin B receptor-deficient rats develop severe hypertension and progressive renal failure. J Am Soc Nephrol (2006) 17:1082–1089.[Abstract/Free Full Text]
  27. Amann K, Rump LC, Simonaviciene A, et al. Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats. J Am Soc Nephrol (2000) 11:1469–1478.[Abstract/Free Full Text]
  28. Vonend O, Apel T, Amann K, et al. Modulation of gene expression by moxonidine in rats with chronic renal failure. Nephrol Dial Transplant (2004) 19:2217–2222.[Abstract/Free Full Text]
  29. Amann K, Koch A, Hofstetter J, et al. Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers. Kidney Int (2001) 60:1309–1323.[CrossRef][Web of Science][Medline]
  30. Pawluczyk IZ, Patel SR, Harris KP. The role of the alpha-1 adrenoceptor in modulating human mesangial cell matrix production. Nephrol Dial Transplant (2006) 21:2417–2424.[Abstract/Free Full Text]
  31. Elzinga LW, Rosen S, Burdmann EA, Hatton DC, Lindsley J, Bennett WM. The role of renal sympathetic nerves in experimental chronic cyclosporine nephropathy. Transplantation (2000) 69:2149–2153.[CrossRef][Web of Science][Medline]
  32. Orth SR. Smoking and the kidney. J Am Soc Nephrol (2002) 13:1663–1672.[Free Full Text]
  33. Odoni G, Ogata H, Viedt C, Amann K, Ritz E, Orth SR. Cigarette smoke condensate aggravates renal injury in the renal ablation model. Kidney Int (2002) 61:2090–2098.[CrossRef][Web of Science][Medline]
  34. Elliot SJ, Karl M, Berho M, et al. Smoking induces glomerulosclerosis in aging estrogen-deficient mice through cross-talk between TGF-beta1 and IGF-I signaling pathways. J Am Soc Nephrol (2006) 17:3315–3324.[Abstract/Free Full Text]
  35. Bennett WM, Walker RG, Henry JP, Kincaid-Smith P. Chronic interstitial nephropathy in mice induced by psychosocial stress: potentiation by caffeine. Nephron (1983) 34:110–113.[Web of Science][Medline]
  36. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med (2006) 144:21–28.[Abstract/Free Full Text]
  37. Abrass CK. Lipid metabolism and renal disease. Contrib Nephrol (2006) 151:106–121.[Web of Science][Medline]
  38. Kramer H. Obesity and chronic kidney disease. Contrib Nephrol (2006) 151:1–18.[Web of Science][Medline]
  39. Lavaud S, Poirier B, Mandet C, et al. Inflammation is probably not a prerequisite for renal interstitial fibrosis in normoglycemic obese rats. Am J Physiol Renal Physiol (2001) 280:F683–F694.[Abstract/Free Full Text]
  40. Wolf G, Ziyadeh FN. Leptin and renal fibrosis. Contrib Nephrol (2006) 151:175–83.[Web of Science][Medline]
  41. Chade AR, Mushin OP, Zhu X, et al. Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia. Hypertension (2005) 46:772–779.[Abstract/Free Full Text]
  42. Joles JA, Kunter U, Janssen U, et al. Early mechanisms of renal injury in hypercholesterolemic or hypertriglyceridemic rats. J Am Soc Nephrol (2000) 11:669–683.[Abstract/Free Full Text]
  43. Li C, Sun BK, Lim SW, et al. Combined effects of losartan and pravastatin on interstitial inflammation and fibrosis in chronic cyclosporine-induced nephropathy. Transplantation (2005) 79:1522–1529.[CrossRef][Web of Science][Medline]
  44. Li C, Yang CW, Park JH, et al. Pravastatin treatment attenuates interstitial inflammation and fibrosis in a rat model of chronic cyclosporine-induced nephropathy. Am J Physiol Renal Physiol (2004) 286:F46–F57.[Abstract/Free Full Text]
  45. Vieira JM Jr, Mantovani E, Rodrigues LT, et al. Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction. Nephrol Dial Transplant (2005) 20:1582–1591.[Abstract/Free Full Text]
  46. Agarwal R. Effects of statins on renal function. Am J Cardiol (2006) 97:748–55.[CrossRef][Web of Science][Medline]
  47. Fujihara CK, De Lourdes NI, Malheiros AGR, de Oliveira IB, Zatz R. Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney. J Am Soc Nephrol (2000) 11:283–290.[Abstract/Free Full Text]
  48. Goncalves RG, Biato MA, Colosimo RD, et al. Effects of mycophenolate mofetil and lisinopril on collagen deposition in unilateral ureteral obstruction in rats. Am J Nephrol (2004) 24:527–536.[CrossRef][Web of Science][Medline]
  49. Kramer S, Loof T, Martini S, et al. Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril. Am J Physiol Renal Physiol (2005) 289:F359–F368.[Abstract/Free Full Text]
  50. Romero F, Rodriguez-Iturbe B, Parra G, Gonzalez L, Herrera-Acosta J, Tapia E. Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats. Kidney Int (1999) 55:945–955.[CrossRef][Web of Science][Medline]
  51. Gwinner W, Mengel M, Franz I, et al. Effect of mycophenolate mofetil (mmf) on tubulointerstitial fibrosis and tubular atrophy in renal allograft recipients studied by protocol biopsies. Transplantation (2006) 82:663–664.[Web of Science][Medline]
  52. Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant (2004) 4:953–961.[CrossRef][Web of Science][Medline]
  53. Wu MJ, Wen MC, Chiu YT, et al. Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int (2006) 69:2029–2036.[CrossRef][Web of Science][Medline]
  54. Peters H, Martini S, Wang Y, et al. Selective lymphocyte inhibition by FTY720 slows the progressive course of chronic anti-thy 1 glomerulosclerosis. Kidney Int (2004) 66:1434–1443.[CrossRef][Web of Science][Medline]
  55. Muller DN, Shagdarsuren E, Park JK, et al. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol (2002) 161:1679–1693.[Abstract/Free Full Text]
  56. Suzuki K, Kanabayashi T, Nakayama H, Doi K. Effects of tacrolimus and dexamethasone on tubulointerstitial fibrosis in mercuric chloride treated Brown Norway rats. Exp Toxicol Pathol (2003) 55:197–207.[CrossRef][Web of Science][Medline]
  57. Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol (2007) 292:F905–F911.[Abstract/Free Full Text]
  58. Aoyama T, Yamamoto S, Kanematsu A, Ogawa O, Tabata Y. Local delivery of matrix metalloproteinase gene prevents the onset of renal sclerosis in streptozotocin-induced diabetic mice. Tissue Eng (2003) 9:1289–1299.[CrossRef][Web of Science][Medline]
  59. Cheng S, Pollock AS, Mahimkar R, Olson JL, Lovett DH. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J (2006) 20:1898–1900.[Abstract/Free Full Text]
  60. Nishida M, Okumura Y, Ozawa S, Shiraishi I, Itoi T, Hamaoka K. MMP-2 inhibition reduces renal macrophage infiltration with increased fibrosis in UUO. Biochem Biophys Res Commun (2007) 354:133–139.[CrossRef][Web of Science][Medline]
  61. Kim H, Oda T, Lopez-Guisa J, et al. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol (2001) 12:736–748.[Abstract/Free Full Text]
  62. Eddy AA, Kim H, Lopez-Guisa J, Oda T, Soloway PD. Interstitial fibrosis in mice with overload proteinuria: deficiency of TIMP-1 is not protective. Kidney Int (2000) 58:618–628.[CrossRef][Web of Science][Medline]
  63. Zhang X, Chen X, Hong Q, et al. TIMP-1 promotes age-related renal fibrosis through upregulating ICAM-1 in human TIMP-1 transgenic mice. J Gerontol A Biol Sci Med Sci (2006) 61:1130–1143.[Abstract/Free Full Text]
  64. Melenhorst WB, van den Heuvel MC, Timmer A, et al. ADAM19 expression in human nephrogenesis and renal disease: associations with clinical and structural deterioration. Kidney Int (2006) 70:1269–1278.[CrossRef][Web of Science][Medline]
  65. Mittaz L, Ricardo S, Martinez G, et al. Neonatal calyceal dilation and renal fibrosis resulting from loss of Adamts-1 in mouse kidney is due to a developmental dysgenesis. Nephrol Dial Transplant (2005) 20:419–423.[Abstract/Free Full Text]
  66. Eddy AA, Fogo AB. Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol (2006) 17:2999–3012.[Free Full Text]
  67. Huang Y, Haraguchi M, Lawrence DA, Border WA, Yu L, Noble NA. A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. J Clin Invest (2003) 112:379–388.[CrossRef][Web of Science][Medline]
  68. Kitching AR, Kong YZ, Huang XR, et al. Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis. J Am Soc Nephrol (2003) 14:1487–1495.[Abstract/Free Full Text]
  69. Krag S, Danielsen CC, Carmeliet P, Nyengaard J, Wogensen L. Plasminogen activator inhibitor-1 gene deficiency attenuates TGF-beta1-induced kidney disease. Kidney Int (2005) 68:2651–2666.[CrossRef][Web of Science][Medline]
  70. Yang J, Shultz RW, Mars WM, et al. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest (2002) 110:1525–1538.[CrossRef][Web of Science][Medline]
  71. Haraguchi M, Border WA, Huang Y, Noble NA. t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Kidney Int (2001) 59:2146–2155.[Web of Science][Medline]
  72. Edgtton KL, Gow RM, Kelly DJ, Carmeliet P, Kitching AR. Plasmin is not protective in experimental renal interstitial fibrosis. Kidney Int (2004) 66:68–76.[CrossRef][Web of Science][Medline]
  73. Zhang G, Kernan KA, Collins SJ, et al. Plasmin(ogen) promotes renal interstitial fibrosis by promoting epithelial-to-mesenchymal transition: role of plasmin-activated signals. J Am Soc Nephrol (2007) 18:846–859.[Abstract/Free Full Text]
  74. Kitching AR, Holdsworth SR, Ploplis VA, et al. Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis. J Exp Med (1997) 185:963–968.[CrossRef][Web of Science][Medline]
  75. Hertig A, Berrou J, Allory Y, et al. Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta. FASEB J (2003) 17:1904–1906.[Abstract/Free Full Text]
  76. Johnson TS, El-Koraie AF, Skill NJ, et al. Tissue transglutaminase and the progression of human renal scarring. J Am Soc Nephrol (2003) 14:2052–2062.[Abstract/Free Full Text]
  77. Skill NJ, Johnson TS, Coutts IG, et al. Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells. J Biol Chem (2004) 279:47754–47762.[Abstract/Free Full Text]
  78. Sebekova K, Dammrich J, Fierlbeck W, Krivosikova Z, Paczek L, Heidland A. Effect of chronic therapy with proteolytic enzymes on hypertension-induced renal injury in the rat model of Goldblatt hypertension. Am J Nephrol (1998) 18:570–576.[CrossRef][Web of Science][Medline]
  79. Sebekova K, Paczek L, Dammrich J, et al. Effects of protease therapy in the remnant kidney model of progressive renal failure. Miner Electrolyte Metab (1997) 23:291–295.[Web of Science][Medline]
  80. Danielson LA, Welford A, Harris A. Relaxin improves renal function and histology in aging Munich Wistar rats. J Am Soc Nephrol (2006) 17:1325–1333.[Abstract/Free Full Text]
  81. Hewitson TD, Mookerjee I, Masterson R, et al. Endogenous relaxin is a naturally occurring modulator of experimental renal tubulointerstitial fibrosis. Endocrinology (2007) 148:660–669.[Abstract/Free Full Text]
  82. Lekgabe ED, Kiriazis H, Zhao C, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension (2005) 46:412–418.[Abstract/Free Full Text]
  83. Samuel CS, Hewitson TD. Relaxin in cardiovascular and renal disease. Kidney Int (2006) 69:1498–1502.[CrossRef][Web of Science][Medline]
  84. Seibold JR. Relaxins: lessons and limitations. Curr Rheumatol Rep (2002) 4:275–276.[CrossRef][Medline]
  85. Leh S, Vaagnes O, Margolin SB, Iversen BM, Forslund T. Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant (2005) 20:71–82.[Abstract/Free Full Text]
  86. Negri AL. Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents. J Nephrol (2004) 17:496–503.[Web of Science][Medline]
  87. Chen X, Moeckel G, Morrow JD, et al. Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury. Am J Pathol (2004) 165:617–630.[Abstract/Free Full Text]
  88. Cosgrove D, Rodgers K, Meehan D, et al. Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol (2000) 157:1649–1659.[Abstract/Free Full Text]
  89. Cook HT, Khan SB, Allen A, et al. Treatment with an antibody to VLA-1 integrin reduces glomerular and tubulointerstitial scarring in a rat model of crescentic glomerulonephritis. Am J Pathol (2002) 161:1265–1272.[Abstract/Free Full Text]
  90. Kagami S, Urushihara M, Kondo S, et al. Effects of anti-alpha1 integrin subunit antibody on anti-Thy-1 glomerulonephritis. Lab Invest (2002) 82:1219–27.[Web of Science][Medline]
  91. Ma LJ, Yang H, Gaspert A, et al. Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice. Am J Pathol (2003) 163:1261–1273.[Abstract/Free Full Text]
  92. Hahm K, Lukashev ME, Luo Y, et al. {alpha}v{beta}6 Integrin regulates renal fibrosis and inflammation in alport mouse. Am J Pathol (2007) 170:110–125.[Abstract/Free Full Text]
  93. Hartner A, Cordasic N, Klanke B, Muller U, Sterzel RB, Hilgers KF. The alpha8 integrin chain affords mechanical stability to the glomerular capillary tuft in hypertensive glomerular disease. Am J Pathol (2002) 160:861–867.[Abstract/Free Full Text]
  94. Blattner SM, Kretzler M. Integrin-linked kinase in renal disease: connecting cell-matrix interaction to the cytoskeleton. Curr Opin Nephrol Hypertens (2005) 14:404–410.[Web of Science][Medline]
  95. Li Y, Yang J, Dai C, Wu C, Liu Y. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest (2003) 112:503–516.[CrossRef][Web of Science][Medline]
  96. Couser WG, Ochi RF, Baker PJ, Schulze M, Campbell C, Johnson RJ. C6 depletion reduces proteinuria in experimental nephropathy induced by a nonglomerular antigen. J Am Soc Nephrol (1991) 2:894–901.[Abstract]
  97. Morita Y, Nomura A, Yuzawa Y, et al. The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis. J Am Soc Nephrol (1997) 8:1363–1372.[Abstract]
  98. Nomura A, Morita Y, Maruyama S, et al. Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. Am J Pathol (1997) 151:539–547.[Abstract]
  99. Rangan GK, Pippin JW, Couser WG. C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis. Kidney Int (2004) 66:1838–1848.[CrossRef][Web of Science][Medline]
  100. Rangan GK, Pippin JW, Coombes JD, Couser WG. C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria. Kidney Int (2005) 67:492–503.[CrossRef][Web of Science][Medline]
  101. Bao L, Wang Y, Chang A, et al. Unrestricted c3 activation occurs in crry-deficient kidneys and rapidly leads to chronic renal failure. J Am Soc Nephrol (2007) 18:811–822.[Abstract/Free Full Text]
  102. Hori Y, Yamada K, Hanafusa N, et al. Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria. Kidney Int (1999) 56:2096–2106.[CrossRef][Web of Science][Medline]
  103. He C, Imai M, Song H, Quigg RJ, Tomlinson S. Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for C5b-9. J Immunol (2005) 174:5750–5757.[Abstract/Free Full Text]
  104. Bao L, Zhou J, Holers VM, Quigg RJ. Excessive matrix accumulation in the kidneys of MRL/lpr lupus mice is dependent on complement activation. J Am Soc Nephrol (2003) 14:2516–2525.[Abstract/Free Full Text]
  105. Welch TR, Frenzke M, Witte D, Davis AE. C5a is important in the tubulointerstitial component of experimental immune complex glomerulonephritis. Clin Exp Immunol (2002) 130:43–48.[CrossRef][Web of Science][Medline]
  106. Boor P, Konieczny A, Villa L, et al. Complement c5 mediates experimental tubulointerstitial fibrosis. J Am Soc Nephrol (2007) 18:1508–1515.[Abstract/Free Full Text]
  107. Bao L, Osawe I, Puri T, Lambris JD, Haas M, Quigg RJ. C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist. Eur J Immunol (2005) 35:2496–2506.[CrossRef][Web of Science][Medline]
  108. Wenderfer SE, Ke B, Hollmann TJ, Wetsel RA, Lan HY, Braun MC. C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice. J Am Soc Nephrol (2005) 16:3572–3582.[Abstract/Free Full Text]
  109. Fan JM, Huang XR, Ng YY, et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. Am J Kidney Dis (2001) 37:820–831.[Web of Science][Medline]
  110. Lan HY, Nikolic-Paterson DJ, Mu W, Vannice JL, Atkins RC. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat. Kidney Int (1995) 47:1303–1309.[Web of Science][Medline]
  111. Taal MW, Zandi-Nejad K, Weening B, et al. Proinflammatory gene expression and macrophage recruitment in the rat remnant kidney. Kidney Int (2000) 58:1664–1676.[CrossRef][Web of Science][Medline]
  112. Vesey DA, Cheung CW, Cuttle L, Endre ZA, Gobe G, Johnson DW. Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production. Kidney Int (2002) 62:31–40.[CrossRef][Web of Science][Medline]
  113. Yamagishi H, Yokoo T, Imasawa T, Mitarai T, Kawamura T, Utsunomiya Y. Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy. J Immunol (2001) 166:609–616.[Abstract/Free Full Text]
  114. Svensson M, Irjala H, Alm P, Holmqvist B, Lundstedt AC, Svanborg C. Natural history of renal scarring in susceptible mIL-8Rh-/- mice. Kidney Int (2005) 67:103–110.[CrossRef][Web of Science][Medline]
  115. Mu W, Ouyang X, Agarwal A, et al. IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease. J Am Soc Nephrol (2005) 16:3651–3660.[Abstract/Free Full Text]
  116. Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy–review of a new approach. Pharmacol Rev (2003) 55:241–269.[Abstract/Free Full Text]
  117. Cook HT, Singh SJ, Wembridge DE, Smith J, Tam FW, Pusey CD. Interleukin-4 ameliorates crescentic glomerulonephritis in Wistar Kyoto rats. Kidney Int (1999) 55:1319–1326.[CrossRef][Web of Science][Medline]
  118. Strutz F, Heeg M, Kochsiek T, Siemers G, Zeisberg M, Muller GA. Effects of pentoxifylline, pentifylline and gamma-interferon on proliferation, differentiation, and matrix synthesis of human renal fibroblasts. Nephrol Dial Transplant (2000) 15:1535–1546.[Abstract/Free Full Text]
  119. Oldroyd SD, Thomas GL, Gabbiani G, El Nahas AM. Interferon-gamma inhibits experimental renal fibrosis. Kidney Int (1999) 56:2116–2127.[CrossRef][Web of Science][Medline]
  120. Johnson RJ, Lombardi D, Eng E, et al. Modulation of experimental mesangial proliferative nephritis by interferon-gamma. Kidney Int (1995) 47:62–69.[Web of Science][Medline]
  121. Dogukan A, Akpolat N, Celiker H, Ilhan N, Halil Bahcecioglu I, Gunal AI. Protective effect of interferon-alpha on carbon tetrachloride-induced nephrotoxicity. J Nephrol (2003) 16:81–84.[Web of Science][Medline]
  122. Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S. Contributions of angiotensin II and tumor necrosis factor-alpha to the development of renal fibrosis. Am J Physiol Renal Physiol (2001) 280:F777–F785.[Abstract/Free Full Text]
  123. Khan SB, Cook HT, Bhangal G, Smith J, Tam FW, Pusey CD. Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis. Kidney Int (2005) 67:1812–1820.[CrossRef][Web of Science][Medline]
  124. Meldrum KK, Misseri R, Metcalfe P, Dinarello CA, Hile KL, Meldrum DR. TNF-{alpha} neutralization ameliorates obstruction-induced renal fibrosis and dysfunction. Am J Physiol Regul Integr Comp Physiol (2007) 292:R1456–R1464.[Abstract/Free Full Text]
  125. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA (2006) 295:2275–2285.[Abstract/Free Full Text]
  126. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation (2004) 109:1594–1602.[Abstract/Free Full Text]
  127. Kitagawa K, Wada T, Furuichi K, et al. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol (2004) 165:237–246.[Abstract/Free Full Text]
  128. Lloyd CM, Minto AW, Dorf ME, et al. RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis. J Exp Med (1997) 185:1371–1380.[Abstract/Free Full Text]
  129. Okada H, Moriwaki K, Kalluri R, et al. Inhibition of monocyte chemoattractant protein-1 expression in tubular epithelium attenuates tubulointerstitial alteration in rat Goodpasture syndrome. Kidney Int (2000) 57:927–936.[CrossRef][Web of Science][Medline]
  130. Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR. Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. J Exp Med (1999) 190:1813–1824.[Abstract/Free Full Text]
  131. Tesch GH, Schwarting A, Kinoshita K, Lan HY, Rollins BJ, Kelley VR. Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis. J Clin Invest (1999) 103:73–80.[Web of Science][Medline]
  132. Vielhauer V, Anders HJ, Mack M, et al. Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. J Am Soc Nephrol (2001) 12:1173–1187.[Abstract/Free Full Text]
  133. Wada T, Furuichi K, Sakai N, et al. Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol (2004) 15:940–948.[Abstract/Free Full Text]
  134. Anders HJ, Vielhauer V, Frink M, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest (2002) 109:251–259.[CrossRef][Web of Science][Medline]
  135. Eis V, Luckow B, Vielhauer V, et al. Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction. J Am Soc Nephrol (2004) 15:337–347.[Abstract/Free Full Text]
  136. Ninichuk V, Gross O, Reichel C, et al. Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease. J Am Soc Nephrol (2005) 16:977–985.[Abstract/Free Full Text]
  137. Vielhauer V, Berning E, Eis V, et al. CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int (2004) 66:2264–2278.[CrossRef][Web of Science][Medline]
  138. Lenda DM, Kikawada E, Stanley ER, Kelley VR. Reduced macrophage recruitment, proliferation, and activation in colony-stimulating factor-1-deficient mice results in decreased tubular apoptosis during renal inflammation. J Immunol (2003) 170:3254–3262.[Abstract/Free Full Text]
  139. Ophascharoensuk V, Giachelli CM, Gordon K, et al. Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int (1999) 56:571–580.[CrossRef][Web of Science][Medline]
  140. Panzer U, Thaiss F, Zahner G, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int (2001) 59:1762–1769.[CrossRef][Web of Science][Medline]
  141. Yoo KH, Thornhill BA, Forbes MS, et al. Osteopontin regulates renal apoptosis and interstitial fibrosis in neonatal chronic unilateral ureteral obstruction. Kidney Int (2006) 70:1735–1741.[CrossRef][Web of Science][Medline]
  142. Furuichi K, Gao JL, Murphy PM. Chemokine receptor CX3CR1 regulates renal interstitial fibrosis after ischemia-reperfusion injury. Am J Pathol (2006) 169:372–387.[Abstract/Free Full Text]
  143. Sakai N, Wada T, Yokoyama H, et al. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA (2006) 103:14098–14103.[Abstract/Free Full Text]
  144. Topham PS, Csizmadia V, Soler D, et al. Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis. J Clin Invest (1999) 104:1549–1557.[Web of Science][Medline]
  145. Bird JE, Giancarli MR, Kurihara T, et al. Increased severity of glomerulonephritis in C-C chemokine receptor 2 knockout mice. Kidney Int (2000) 57:129–136.[CrossRef][Web of Science][Medline]
  146. Barber DF, Bartolome A, Hernandez C, et al. PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med (2005) 11:933–935.[Web of Science][Medline]
  147. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol (2002) 13:2600–2610.[Abstract/Free Full Text]
  148. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature (1992) 359:693–699.[CrossRef][Medline]
  149. Yu L, Border WA, Huang Y, Noble NA. TGF-beta isoforms in renal fibrogenesis. Kidney Int (2003) 64:844–856.[CrossRef][Web of Science][Medline]
  150. Terada Y, Hanada S, Nakao A, Kuwahara M, Sasaki S, Marumo F. Gene transfer of Smad7 using electroporation of adenovirus prevents renal fibrosis in post-obstructed kidney. Kidney Int (2002) 61:94–98.[Medline]
  151. Lan HY, Mu W, Tomita N, et al. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol (2003) 14:1535–1548.[Abstract/Free Full Text]
  152. Hou CC, Wang W, Huang XR, et al. Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-beta signaling and fibrosis in rat remnant kidney. Am J Pathol (2005) 166:761–71.[Abstract/Free Full Text]
  153. Inazaki K, Kanamaru Y, Kojima Y, et al. Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Kidney Int (2004) 66:597–604.[CrossRef][Web of Science][Medline]
  154. Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest (2003) 112:1486–1494.[CrossRef][Web of Science][Medline]
  155. Nagler A, Katz A, Aingorn H, et al. Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone. Kidney Int (1997) 52:1561–1569.[Web of Science][Medline]
  156. Boutet A, De Frutos CA, Maxwell PH, Mayol MJ, Romero J, Nieto MA. Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. Embo J (2006) 25:5603–5613.[CrossRef][Web of Science][Medline]
  157. Fukasawa H, Yamamoto T, Togawa A, et al. Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney Int (2006) 69:1733–1740.[CrossRef][Web of Science][Medline]
  158. Yang J, Zhang X, Li Y, Liu Y. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling. J Am Soc Nephrol (2003) 14:3167–3177.[Abstract/Free Full Text]
  159. Moon JA, Kim HT, Cho IS, Sheen YY, Kim DK. IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int (2006) 70:1234–1243.[CrossRef][Web of Science][Medline]
  160. Grygielko ET, Martin WM, Tweed C, et al. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther (2005) 313:943–951.[Abstract/Free Full Text]
  161. Li J, Campanale NV, Liang RJ, Deane JA, Bertram JF, Ricardo SD. Inhibition of p38 mitogen-activated protein kinase and transforming growth factor-beta1/Smad signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy. Am J Pathol (2006) 169:1527–1540.[Abstract/Free Full Text]
  162. Prakash J, Sandovici M, Saluja V, et al. Intracellular delivery of the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] in renal tubular cells: a novel strategy to treat renal fibrosis. J Pharmacol Exp Ther (2006) 319:8–19.[Abstract/Free Full Text]
  163. Stambe C, Atkins RC, Tesch GH, Masaki T, Schreiner GF, Nikolic-Paterson DJ. The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis. J Am Soc Nephrol (2004) 15:370–379.[Abstract/Free Full Text]
  164. Schaefer L, Macakova K, Raslik I, et al. Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction. Am J Pathol (2002) 160:1181–1191.[Abstract/Free Full Text]
  165. Isaka Y, Brees DK, Ikegaya K, et al. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med (1996) 2:418–423.[CrossRef][Web of Science][Medline]
  166. Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med (2003) 9:964–968.[CrossRef][Web of Science][Medline]
  167. Zeisberg M, Bottiglio C, Kumar N, et al. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol (2003) 285:F1060–F1067.[Abstract/Free Full Text]
  168. Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem (2005) 280:8094–8100.[Abstract/Free Full Text]
  169. Hruska KA, Guo G, Wozniak M, et al. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am J Physiol Renal Physiol (2000) 279:F130–F143.[Abstract/Free Full Text]
  170. Wang S, Chen Q, Simon TC, et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int (2003) 63:2037–2049.[CrossRef][Web of Science][Medline]
  171. Li T, Surendran K, Zawaideh MA, Mathew S, Hruska KA. Bone morphogenetic protein 7: a novel treatment for chronic renal and bone disease. Curr Opin Nephrol Hypertens (2004) 13:417–422.[CrossRef][Web of Science][Medline]
  172. Zeisberg M. Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol Dial Transplant (2006) 21:568–573.[Free Full Text]
  173. Ikeda Y, Jung YO, Kim H, et al. Exogenous bone morphogenetic protein-7 fails to attenuate renal fibrosis in rats with overload proteinuria. Nephron Exp Nephrol (2004) 97:e123–e135.[CrossRef][Medline]
  174. Lin J, Patel SR, Cheng X, et al. Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease. Nat Med (2005) 11:387–393.[CrossRef][Web of Science][Medline]
  175. Yanagita M. Modulator of bone morphogenetic protein activity in the progression of kidney diseases. Kidney Int (2006) 70:989–993.[CrossRef][Web of Science][Medline]
  176. Herrero-Fresneda I, Torras J, Franquesa M, et al. HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms. Kidney Int (2006) 70:265–274.[CrossRef][Web of Science][Medline]
  177. Liu Y. Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action. Am J Physiol Renal Physiol (2004) 287:F7–F16.[Abstract/Free Full Text]
  178. Mizuno S, Kurosawa T, Matsumoto K, Mizuno-Horikawa Y, Okamoto M, Nakamura T. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease. J Clin Invest (1998) 101:1827–1834.[Web of Science][Medline]
  179. Mizuno S, Matsumoto K, Nakamura T. Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int (2001) 59:1304–1314.[CrossRef][Web of Science][Medline]
  180. Takayama H, LaRochelle WJ, Sabnis SG, Otsuka T, Merlino G. Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor. Lab Invest (1997) 77:131–138.[Web of Science][Medline]
  181. Wang SN, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int (2000) 57:1002–1014.[CrossRef][Web of Science][Medline]
  182. Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T. Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol (2005) 53:35–69.[Web of Science][Medline]
  183. Abdel WN, Mason RM. Connective tissue growth factor and renal diseases: some answers, more questions. Curr Opin Nephrol Hypertens (2004) 13:53–58.[CrossRef][Web of Science][Medline]
  184. van Nieuwenhoven FA, Jensen LJ, Flyvbjerg A, Goldschmeding R. Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point? Nephrol Dial Transplant (2005) 20:6–10.[Free Full Text]
  185. Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol (2006) 17:2484–2494.[Abstract/Free Full Text]
  186. Okada H, Kikuta T, Kobayashi T, et al. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol (2005) 16:133–143.[Abstract/Free Full Text]
  187. Yokoi H, Mukoyama M, Nagae T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol (2004) 15:1430–1440.[Abstract/Free Full Text]
  188. Zhou G, Li C, Cai L. Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. Am J Pathol (2004) 165:2033–2043.[Abstract/Free Full Text]
  189. Kang DH, Johnson RJ. Vascular endothelial growth factor: a new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens (2003) 12:43–49.[CrossRef][Web of Science][Medline]
  190. Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol (2001) 12:1448–1457.[Abstract/Free Full Text]
  191. Kang DH, Kim YG, Andoh TF, et al. Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor. Am J Physiol Renal Physiol (2001) 280:F727–F736.[Abstract/Free Full Text]
  192. Hara A, Wada T, Furuichi K, et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int (2006) 69:1986–1995.[CrossRef][Web of Science][Medline]
  193. Ostendorf T, Kunter U, Eitner F, et al. VEGF(165) mediates glomerular endothelial repair. J Clin Invest (1999) 104:913–923.[Web of Science][Medline]
  194. de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol (2001) 12:993–1000.[Abstract/Free Full Text]
  195. Schrijvers BF, Flyvbjerg A, Tilton RG, Rasch R, Lameire NH, De Vriese AS. Pathophysiological role of vascular endothelial growth factor in the remnant kidney. Nephron Exp Nephrol (2005) 101:e9–e15.[CrossRef][Medline]
  196. Schrijvers BF, Rasch R, Tilton RG, Flyvbjerg A. High protein-induced glomerular hypertrophy is vascular endothelial growth factor-dependent. Kidney Int (2002) 61:1600–1604.[CrossRef][Web of Science][Medline]
  197. Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, Schrijvers BF, Tilton RG, Rasch R. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes (2002) 51:3090–3094.[Abstract/Free Full Text]
  198. Herbst RS. Toxicities of antiangiogenic therapy in non-small-cell lung cancer. Clin Lung Cancer (2006) 8 [Suppl 1]:S23–S30.
  199. Floege J, Eitner F, Alpers CE. A new look at platelet-derived growth factor and renal disease. J Am Soc Nephrol (2007) in press.
  200. Ostendorf T, Kunter U, Grone HJ, et al. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol (2001) 12:909–918.[Abstract/Free Full Text]
  201. Tang WW, Ulich TR, Lacey DL, et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol (1996) 148:1169–1180.[Abstract]
  202. Taneda S, Hudkins KL, Topouzis S, et al. Obstructive uropathy in mice and humans: potential role for PDGF-D in the progression of tubulointerstitial injury. J Am Soc Nephrol (2003) 14:2544–2555.[Abstract/Free Full Text]
  203. Ostendorf T, Rong S, Boor P, et al. Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol (2006) 17:1054–1062.[Abstract/Free Full Text]
  204. Boor P, Konieczny A, Villa L, et al. PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrol Dial Transplant (2007) 22:1323–1331.[Abstract/Free Full Text]
  205. Eitner F, Ostendorf T, Kretzler M, et al. PDGF-C expression in the developing and normal adult human kidney and in glomerular diseases. J Am Soc Nephrol (2003) 14:1145–1153.[Abstract/Free Full Text]
  206. Eitner F, Ostendorf T, Van Roeyen C, et al. Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. J Am Soc Nephrol (2002) 13:910–917.[Abstract/Free Full Text]
  207. Wang S, Wilkes MC, Leof EB, Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. FASEB J (2005) 19:1–11.[Abstract/Free Full Text]
  208. Lassila M, Jandeleit-Dahm K, Seah KK, et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol (2005) 16:363–373.[Abstract/Free Full Text]
  209. Savikko J, Taskinen E, Von Willebrand E. Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy. Transplantation (2003) 75:1147–1153.[CrossRef][Web of Science][Medline]
  210. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med (2006) 12:908–916.[CrossRef][Web of Science][Medline]
  211. Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med (2006) 354:2006–2013.[Abstract/Free Full Text]
  212. Floege J, Kriz W, Schulze M, et al. Basic fibroblast growth factor augments podocyte injury and induces glomerulosclerosis in rats with experimental membranous nephropathy. J Clin Invest (1995) 96:2809–2819.[Web of Science][Medline]
  213. Strutz F, Zeisberg M, Hemmerlein B, et al. Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int (2000) 57:1521–1538.[CrossRef][Web of Science][Medline]
  214. Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int (2002) 61:1714–1728.[CrossRef][Web of Science][Medline]
  215. Rossini M, Cheunsuchon B, Donnert E, et al. Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney Int (2005) 68:2621–2628.[CrossRef][Web of Science][Medline]
  216. Francois H, Placier S, Flamant M, et al. Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition. FASEB J (2004) 18:926–928.[Abstract/Free Full Text]
  217. Terzi F, Burtin M, Hekmati M, et al. Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury. J Clin Invest (2000) 106:225–234.[Web of Science][Medline]
  218. Lautrette A, Li S, Alili R, et al. Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat Med (2005) 11:867–874.[CrossRef][Web of Science][Medline]
  219. Morrissey JJ, Ishidoya S, McCracken R, Klahr S. Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy. J Am Soc Nephrol (1996) 7:2202–2212.[Abstract]
  220. Peters H, Daig U, Martini S, et al. NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis. Kidney Int (2003) 64:509–518.[CrossRef][Web of Science][Medline]
  221. Reyes AA, Purkerson ML, Karl I, Klahr S. Dietary supplementation with L-arginine ameliorates the progression of renal disease in rats with subtotal nephrectomy. Am J Kidney Dis (1992) 20:168–176.[Web of Science][Medline]
  222. Peters H, Border WA, Ruckert M, Kramer S, Neumayer HH, Noble NA. L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis. Kidney Int (2003) 63:1382–1392.[CrossRef][Web of Science][Medline]
  223. Rangan GK, Wang Y, Harris DC. Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats. J Am Soc Nephrol (2001) 12:1696–1705.[Abstract/Free Full Text]
  224. Chang B, Mathew R, Palmer LS, Valderrama E, Trachtman H. Nitric oxide in obstructive uropathy: role of endothelial nitric oxide synthase. J Urol (2002) 168:1801–1804.[CrossRef][Web of Science][Medline]
  225. Hochberg D, Johnson CW, Chen J, et al. Interstitial fibrosis of unilateral ureteral obstruction is exacerbated in kidneys of mice lacking the gene for inducible nitric oxide synthase. Lab Invest (2000) 80:1721–1728.[Web of Science][Medline]
  226. Ito K, Chen J, Khodadadian JJ, et al. Liposome-mediated transfer of nitric oxide synthase gene improves renal function in ureteral obstruction in rats. Kidney Int (2004) 66:1365–75.[CrossRef][Web of Science][Medline]
  227. Forbes MS, Thornhill BA, Park MH, Chevalier RL. Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury. Am J Pathol (2007) 170:87–99.[Abstract/Free Full Text]
  228. Wang Y, Kramer S, Loof T, et al. Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis. Kidney Int (2005) 68:47–61.[CrossRef][Web of Science][Medline]
  229. Rodriguez-Iturbe B, Ferrebuz A, Vanegas V, et al. Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage. Kidney Int (2005) 68:2131–2142.[CrossRef][Web of Science][Medline]
  230. Lin SL, Chen RH, Chen YM, et al. Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol (2005) 16:2702–2713.[Abstract/Free Full Text]
  231. Wang Y, Kramer S, Loof T, et al. Enhancing cGMP in experimental progressive renal fibrosis: soluble guanylate cyclase stimulation vs. phosphodiesterase inhibition. Am J Physiol Renal Physiol (2006) 290:F167–F176.[Abstract/Free Full Text]
  232. Lange-Sperandio B, Forbes MS, Thornhill B, Okusa MD, Linden J, Chevalier RL. A2A adenosine receptor agonist and PDE4 inhibition delays inflammation but fails to reduce injury in experimental obstructive nephropathy. Nephron Exp Nephrol (2005) 100:e113–e123.[CrossRef][Medline]
  233. Tamada S, Asai T, Kuwabara N, et al. Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis. J Pharmacol Sci (2006) 100:17–21.[CrossRef][Web of Science][Medline]
  234. Kuwabara N, Tamada S, Iwai T, et al. Attenuation of renal fibrosis by curcumin in rat obstructive nephropathy. Urology (2006) 67:440–446.[CrossRef][Web of Science][Medline]
  235. Kanda T, Wakino S, Hayashi K, Homma K, Ozawa Y, Saruta T. Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kidney Int (2003) 64:2009–2019.[CrossRef][Web of Science][Medline]
  236. Nagatoya K, Moriyama T, Kawada N, et al. Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int (2002) 61:1684–1695.[CrossRef][Web of Science][Medline]
  237. Nishikimi T, Akimoto K, Wang X, et al. Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. J Hypertens (2004) 22:1787–1796.[CrossRef][Web of Science][Medline]
  238. Patel S, Takagi KI, Suzuki J, et al. RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation. J Am Soc Nephrol (2005) 16:1977–1984.[Abstract/Free Full Text]
  239. Lai A, Frishman WH. Rho-kinase inhibition in the therapy of cardiovascular disease. Cardiol Rev (2005) 13:285–292.[CrossRef][Medline]
  240. Fu P, Liu F, Su S, et al. Signaling mechanism of renal fibrosis in unilateral ureteral obstructive kidney disease in ROCK1 knockout mice. J Am Soc Nephrol (2006) 17:3105–3114.[Abstract/Free Full Text]
  241. Little MH. Regrow or repair: potential regenerative therapies for the kidney. J Am Soc Nephrol (2006) 17:2390–2401.[Abstract/Free Full Text]
  242. Prodromidi EI, Poulsom R, Jeffery R, et al. Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. Stem Cells (2006) 24:2448–2455.[CrossRef][Web of Science][Medline]
  243. Ninichuk V, Gross O, Segerer S, et al. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int (2006) 70:121–129.[CrossRef][Web of Science][Medline]
  244. Sugimoto H, Mundel TM, Sund M, Xie L, Cosgrove D, Kalluri R. Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease. Proc Natl Acad Sci USA (2006) 103:7321–7326.[Abstract/Free Full Text]
  245. Broekema M, Harmsen MC, van Luyn MJ, et al. Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J Am Soc Nephrol (2007) 18:165–175.[Abstract/Free Full Text]
  246. Kunter U, Rong S, Boor P, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol (2007) 18: 1754–1764; doi:10.1681/ASN.2007010044.
  247. Akahori H, Ota T, Torita M, Ando H, Kaneko S, Takamura T. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression. J Pharmacol Exp Ther (2005) 314:514–521.[Abstract/Free Full Text]
  248. Kelly DJ, Zhang Y, Gow R, Gilbert RE. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol (2004) 15:2619–2629.[Abstract/Free Full Text]
  249. Kelly DJ, Zhang Y, Cox AJ, Gilbert RE. Combination therapy with tranilast and angiotensin-converting enzyme inhibition provides additional renoprotection in the remnant kidney model. Kidney Int (2006) 69:1954–1960.[CrossRef][Web of Science][Medline]
  250. Soma J, Sato K, Saito H, Tsuchiya Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant (2006) 21:2795–2799.[Abstract/Free Full Text]
  251. El-Koraie AF, Baddour NM, Adam AG, El Kashef EH, El Nahas AM. Role of stem cell factor and mast cells in the progression of chronic glomerulonephritides. Kidney Int (2001) 60:167–172.[CrossRef][Web of Science][Medline]
  252. Roberts IS, Brenchley PE. Mast cells: the forgotten cells of renal fibrosis. J Clin Pathol (2000) 53:858–862.[Abstract/Free Full Text]
  253. Kondo S, Kagami S, Kido H, Strutz F, Muller GA, Kuroda Y. Role of mast cell tryptase in renal interstitial fibrosis. J Am Soc Nephrol (2001) 12:1668–1676.[Abstract/Free Full Text]
  254. Kanamaru Y, Scandiuzzi L, Essig M, et al. Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis. J Immunol (2006) 176:5607–5615.[Abstract/Free Full Text]
  255. Miyazawa S, Hotta O, Doi N, Natori Y, Nishikawa K, Natori Y. Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats. Kidney Int (2004) 65:2228–37.[CrossRef][Web of Science][Medline]
  256. Timoshanko JR, Kitching R, Semple TJ, Tipping PG, Holdsworth SR. A pathogenetic role for mast cells in experimental crescentic glomerulonephritis. J Am Soc Nephrol (2006) 17:150–159.[Abstract/Free Full Text]
  257. Lin L, Gerth AJ, Peng SL. Susceptibility of mast cell-deficient W/Wv mice to pristane-induced experimental lupus nephritis. Immunol Lett (2004) 91:93–97.[CrossRef][Web of Science][Medline]
  258. Silver RB, Reid AC, Mackins CJ, et al. Mast cells: a unique source of renin. Proc Natl Acad Sci USA (2004) 101:13607–13612.[Abstract/Free Full Text]
  259. Lange-Sperandio B, Cachat F, Thornhill BA, Chevalier RL. Selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice. Kidney Int (2002) 61:516–524.[CrossRef][Web of Science][Medline]
  260. Kuhlmann A, Haas CS, Gross ML, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol (2004) 286:F526–F533.[Abstract/Free Full Text]
  261. Li Y, Spataro BC, Yang J, Dai C, Liu Y. 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int (2005) 68:1500–1510.[CrossRef][Web of Science][Medline]
  262. Tan X, Li Y, Liu Y. Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol (2006) 17:3382–3393.[Abstract/Free Full Text]
  263. Zafiriou S, Stanners SR, Saad S, Polhill TS, Poronnik P, Pollock CA. Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts. J Am Soc Nephrol (2005) 16:638–645.[Abstract/Free Full Text]
  264. Li Y, Wen X, Spataro BC, Hu K, Dai C, Liu Y. hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-gamma agonists. J Am Soc Nephrol (2006) 17:54–65.[Abstract/Free Full Text]
  265. Panchapakesan U, Sumual S, Pollock CA, Chen X. PPARgamma agonists exert antifibrotic effects in renal tubular cells exposed to high glucose. Am J Physiol Renal Physiol (2005) 289:F1153–F1158.[Abstract/Free Full Text]
  266. Schaier M, Jocks T, Grone HJ, Ritz E, Wagner J. Retinoid agonist isotretinoin ameliorates obstructive renal injury. J Urol (2003) 170:1398–1402.[CrossRef][Web of Science][Medline]
  267. Kang DH, Park EY, Yu ES, Lee YS, Yoon KI. Renoprotective effect of erythropoietin (EPO): possibly via an amelioration of renal hypoxia with stimulation of angiogenesis in the kidney. Kidney Int (2005) 67:1683.[CrossRef][Web of Science][Medline]
  268. Lee SH, Li C, Lim SW, et al. Attenuation of interstitial inflammation and fibrosis by recombinant human erythropoietin in chronic cyclosporine nephropathy. Am J Nephrol (2005) 25:64–76.[CrossRef][Medline]
  269. Baggio B, Musacchio E, Priante G. Polyunsaturated fatty acids and renal fibrosis: pathophysiologic link and potential clinical implications. J Nephrol (2005) 18:362–367.[Web of Science][Medline]
  270. Sebekova K, Eifert T, Klassen A, Heidland A, Amann K. Renal effects of S18886 (terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes. Diabetes (2007) 56:968–974.[Abstract/Free Full Text]
  271. Shimizu MH, Coimbra TM, de Araujo M, Menezes LF, Seguro AC. N-acetylcysteine attenuates the progression of chronic renal failure. Kidney Int (2005) 68:2208–2217.[CrossRef][Web of Science][Medline]
  272. Heller F, Lindenmeyer MT, Cohen CD, et al. The contribution of B cells to renal interstitial inflammation. Am J Pathol (2007) 170:457–468.[Abstract/Free Full Text]
  273. Kelly DJ, Chanty A, Gow RM, Zhang Y, Gilbert RE. Protein kinase Cbeta inhibition attenuates osteopontin expression, macrophage recruitment, and tubulointerstitial injury in advanced experimental diabetic nephropathy. J Am Soc Nephrol (2005) 16:1654–1660.[Abstract/Free Full Text]
  274. Kelly DJ, Zhang Y, Hepper C, et al. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes (2003) 52:512–518.[Abstract/Free Full Text]
  275. Meier M, Park JK, Overheu D, et al. Deletion of protein kinase C-{beta} isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. Diabetes (2007) 56:346–354.[Abstract/Free Full Text]
  276. Ohshiro Y, Ma RC, Yasuda Y, et al. Reduction of diabetes-induced oxidative stress, fibrotic cytokine expression, and renal dysfunction in protein kinase Cbeta-null mice. Diabetes (2006) 55:3112–3120.[Abstract/Free Full Text]
  277. Ma FY, Flanc RS, Tesch GH, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol (2007) 18:472–484.[Abstract/Free Full Text]
  278. Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end products and the kidney. Am J Physiol Renal Physiol (2005) 289:F645–F659.[Abstract/Free Full Text]
  279. Li HY, Hou FF, Zhang X, et al. Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J Am Soc Nephrol (2007) 18:528–538.[Abstract/Free Full Text]
  280. Meldrum KK, Misseri R, Metcalfe P, Dinarello CA, Hile KL, Meldrum DR. TNF-{alpha} neutralization ameliorates obstruction-induced renal fibrosis and dysfunction. Am J Physiol Regul Integr Comp Physiol (2006) 292: R1456–R1464; doi: 10.1152/ajpregu.00620.2005.
  281. Chae YM, Park KK, Lee IK, Kim JK, Kim CH, Chang YC. Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction. Gene Ther (2006) 13:430–439.[CrossRef][Web of Science][Medline]
  282. Park SH, Choi MJ, Song IK, et al. Erythropoietin decreases renal fibrosis in mice with ureteral obstruction: role of inhibiting tgf-beta-induced epithelial-to-mesenchymal transition. J Am Soc Nephrol (2007) 18:1497–1507.[Abstract/Free Full Text]
  283. Matsumoto Y, Ueda S, Yamagishi S, et al. Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J Am Soc Nephrol (2007) 18:1525–1533.[Abstract/Free Full Text]
  284. Hudkins KL, Gilbertson DG, Carling M, et al. Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol (2004) 15:286–298.[Abstract/Free Full Text]
  285. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol (2007) 8:221–233.[CrossRef][Web of Science][Medline]
Received for publication: 7. 3.07
Accepted in revised form: 25. 5.07


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