NDT Advance Access originally published online on November 3, 2006
Nephrology Dialysis Transplantation 2007 22(1):109-117; doi:10.1093/ndt/gfl618
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The expression of matrix metalloproteinase-11 protein in various types of glomerulonephritis
12nd Department of Pathology, "Attikon" University Hospital, School of Medicine, The National and Kapodistrian University of Athens, 2Department of Nephrology, "Laikon" General Hospital of Athens, 3Department of Nephrology, General Regional Hospital of Nikea, Piraeus and 4Department of Nephrology, "Tzanio" Regional General Hospital of Piraeus, Greece
Correspondence and offprint requests to: Prof. Dr Lydia Nakopoulou, Department of Pathology, The Athens National University Medical School, 75 Mikras Asias str., Goudi, GR-115 27 Athens, Greece. Email: lnakopou{at}cc.uoa.gr; alazaris{at}med.uoa.gr
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Abstract |
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Background. Matrix metalloproteinases (MMPs) have been implicated to play important roles in a number of pathological processes such as inflammation. In human glomeruli, the mesangial matrix turnover is controlled by a dynamic equilibrium between synthesis and degradation to which metalloproteinases are known to contribute. Metalloproteinase-11 (MMP-11) was originally discovered as a gene whose expression was associated with tissue remodelling. The aim of this study was to investigate whether MMP-11 protein is expressed in various types of glomerulonephritis and to elucidate the role of this expression.
Methods. Using standard immunohistochemistry, we analysed MMP-11 expression in renal biopsies from 95 patients with primary glomerulonephritis (n = 44) and secondary, either lupus-associated glomerulonephritis (n = 22) or pauci-immune, ANCA-associated glomerulonephritis due to small vessel vasculitis (n = 23) or Wegener's granulomatosis (n = 6). The examined cases were divided into two groups (proliferative and non-proliferative). Anti-Ki67 and -CD68 immunostaining was also performed in order to estimate cell proliferation and number of macrophages, respectively.
Results. MMP-11 immunopositivity was detected in the glomeruli of the majority of pathological samples. The highest incidence of MMP-11 immunopositivity (26.3%) was noticed in glomerulonephritides associated with microscopic polyangiitis and Wegener's granulomatosis. Generally, MMP-11 was often expressed in segmental areas of sclerosis, microadhesions, cellular and fibrocellular crescents. Fibrotic crescents and fibrotic glomeruli were constantly MMP-11-immunonegative. In MMP-11 immunoreactive glomeruli, increased numbers of macrophages were often detected in the mesangium (P = 0.001), while no such observation could be made with regard to proliferating cells (P = 0.170).
Conclusions. MMP-11, like an inflammatory mediator, may exert a chemotactic influence on macrophages which aggregate in the mesangium; MMP-11 is not likely to have a parallel mitogenic or antifibrotic effect in diseased glomeruli.
Keywords: glomerulonephritis; immunohistochemistry; macrophages; matrix metalloproteinase-11; microscopic polyangiitis
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Introduction |
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Glomerular extracellular matrixes (ECMs) are composed of mesangial matrix and basement membranes [1]. Leucocyte infiltration inside glomeruli necessitates basement membrane collagen breakdown and leads to mesangiolysis, cell proliferation and ECM synthesis during the repair process as observed during acute glomerulonephritis (GN), vasculitis and acute graft rejection. On the other hand, the histological hallmark of chronic GN or chronic kidney rejection is progressive fibrosis in which ECM turnover (i.e. the imbalance between production and degradation of ECM) plays an important role [2,3]. The degradation of ECM proteins is thought to occur by the action of proteases, notably the matrix metalloproteinases (MMPs). MMPs can be classified into five major groups, i.e. interstitial collagenases, gelatinases, stromelysins, matrilysins and membrane-type-MMPs. MMPs are also involved in the regulation of cell proliferation and possibly of apoptosis [4]. In renal development, MMPs appear to play a role in the phenotypic conversion of a mesenchymal cell population into epithelial cells [5]. In the kidney of the adult, MMPs are synthesized by intrinsic glomerular cells and tubular epithelial cells [4]. There is accumulating evidence that MMPs play a prominent role in glomerular inflammatory diseases either as antifibrotic enzymes or as proinflammatory mediators [6]. Macrophages are important effector cells in both the adaptive and the innate immune response and their accumulation is a prominent feature in most types of human GN [7]; especially in secondary GN due to microscopic polyangiitis, large numbers of macrophages are known to be present in the interstitial tissues of the kidney cortex [8]. Furthermore, it is well known that in ANCA-associated vasculitis, the macrophages are the most important cells in glomerular crescent formation [7,8]. Chemotactic factors promoting macrophage infiltration (and activation) are being investigated [9] since their targeting has proven effective in inhibiting renal macrophage influx. On the other hand, there is a wide range of molecules potentially secreted by stimulated macrophages, such as cytokines, growth factors and metalloproteinases [7]. Macrophages and their products have been implicated in a number of pathological processes in GN.
MMP-11 (stromelysin-3) was originally discovered as a product of a gene whose expression was associated with normal tissue ECM remodelling [10] and with stromal fibroblasts surrounding many invasive carcinomas. MMP-11 is a unique MMP because it is not secreted as a zymogen but is processed by furin within the constitutive secretory pathway [11]. Compared with other MMPs, MMP-11 shows a different molecular structure, different activity, different gene organization and regulation [11]. In particular, MMP-11 has been shown to have only a weak activity toward ECM proteins and probably only an indirect role in ECM remodelling (through activation of serpins). In the present study, we investigated the immunohistochemical expression of MMP-11 in a well-documented series of 95 kidney biopsies from patients with various types of primary or secondary GN as well as in a number of biopsies from transplanted kidneys with lesions of chronic and/or acute rejection; we searched for any possible association between MMP-11 immunoreactivity and a specific group of kidney disease and we made an attempt to link MMP-11 expression pattern with cell proliferation and number of macrophages so that any pathogenetic role of this MMP can be investigated at some extent.
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Subjects and methods |
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Percutaneous renal biopsies were obtained from 44 patients with various types of primary GN and from 51 patients with secondary GN. An adequate number of glomeruli and vessels was available per biopsy (mean number: 13.4; min: 8, max: 28; SD = 1.12). Twenty-two patients of the latter patient category already had a diagnosis of systemic lupus eryhtematosus (SLE) and GN, while the remaining patients with secondary GN had microscopic polyangiitis (n = 23) or active Wegener's granulomatosis (n = 6). Patients with Wegener's granulomatosis were characterized by C-ANCAs (PR3-ANCA) positivity and so were eight patients with microscopic polyangiitis. The majority of the latter patients though, had P-ANCAs (MPO-ANCA) and their main clinical symptoms included renal manifestations, weight loss, skin involvement and fever; all demonstrated an active urine sediment and none had received treatment with steroids and immunosuppressive drugs prior to the biopsy. As a control group, totally normal kidney sections from 10 kidneys resected for renal cell carcinoma were examined; fibroblasts in or around the renal cell carcinomas stained for MMP-11 and served as positive controls.
As far as GNs are concerned, apart from taking into account their primary or secondary nature, the cases were divided into proliferative and non-proliferative ones (Table 1). Further information about the pathological lesions observed in the above samples is given in Table 2. Interstitial fibrosis and tubular atrophy, when noticeable, were minimal to mild. The clinical data available included creatinine serum levels, presence of hypertension, haematuria (microscopic or macroscopic) and proteinuria.
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Immunohistochemical staining was performed on 4 µm thick, formalin-fixed, paraffin sections, using an avidin-biotin immunoperoxidase technique, after overnight heating at 38°C and subsequent deparafinization in xylene and rehydration through graded alcohols. After quenching of endogenous peroxidase activity using a hydrogen peroxide solution (0.3% in TBS for 30 min), we proceeded to autoclave heat-mediated antigen retrieval in 10 mM, pH = 6 citrate buffer and blockage of non-specific binding by incubation in 10% normal horse serum in TBS (Vector Lab, Burlingame, CA, USA) for 30 min at room temperature. Subsequently, sections were incubated overnight, at 4°C in a humidified chamber, with the monoclonal primary antibody 5ST-4A9, raised against the haemopexin-like domain of human MMP-11 (kindly offered to us by Prof. P. Chambon, IGBMC, Strasburg, France) at a dilution of 1:1000 in TBS. This antibody recognizes both the mature form of MMP-11 and its active fragment. The optimal antibody concentration was determined after multiple staining experiments. The two other mouse monoclonal antibodies used in this study were: KP1 (Dako, Glostrup, Denmark), anti-CD68 present in lysosomes of monocytes and macrophages (dilution of 1:50) and MIB1, anti-Ki67 (Dako, Glostrup, Denmark) (dilution of 1:50). Sections were then incubated in biotinylated horse anti-mouse secondary antibody diluted 1:150 in bovine serum albumin, for 30 min at room temperature followed by peroxidase-conjugated avidin-biotin complexes (Vectastain Elite ABC kit, Vector Lab, Burlingame, CA, USA) in a 30 min incubation at room temperature and addition of 3,3'-diaminobenzidine tetrachlorohydrate (DAB), in order to achieve visualization of the requested antigen. Nuclei were counterstained using Harris’ haematoxylin. In cases where the identification of proximal vs distal tubules was difficult, consecutive serial sections were stained so that any remnants of brush border became detectable. Previously, MMP-11-positive breast cancer tissue sections served as additional positive controls in each staining procedure while negative controls included substitution of primary antibody with mouse (non-immune) IgG diluted at the same concentration and applied to serial sections for each biopsy.
In the examined slides, when some degree of MMP-11 immunostaining was noticeable, MMP-11 immunopositivity was recorded. When no staining was observed, the respective cases were characterized as MMP-11 negative. In cases with positive MMP-11 immunoreaction, the specific site of immunostaining within the glomerulus or the interstitial tissue was recorded (Table 2). As negative controls constantly lacked any degreee of immunostaining, non-specific background activity was impossible in the positive samples. The presence of macrophages and proliferating cells was quantitatively evaluated after careful examination of the number of all immunostained cells in each case and, for statistical reasons, it was classified as decreased or increased with the cutoff point of five macrophages per glomerulus. Images from MMP-11 immunopositive cases and the respective high power fields of sections with the anti-CD68 antibody were saved as electronic files in a computer so that the expression of MMP-11 on macrophages could be discriminated from the MMP-11 expression on other cell types (fibroblasts, in particular) by comparative image analysis.
Statistical analysis was performed by chi-square statistics and Fisher's exact test. Statistical significance was set at 5%.
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Results |
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With regard to normal controls, a minimal degree of MMP-11 immunopositivity was occasionally detected in the mesangial matrix of normal glomeruli and in proximal tubules; rarely, tubules’ basement membranes as well as Bowman's capsules were partially stained.
MMP-11 glomerular immunoreactivity was noticed in 76/95 (80%) of all pathological samples; as far as various subgroups are concerned, the highest frequency of MMP-11 immunopositivity status (26.3%) was noticed in the subgroup of secondary pauci-immune, ANCA-positive GNs associated with microscopic polyangiitis and Wegener's granulomatosis. The second highest frequency was observed in the group of primary non-proliferative GNs (21.1%), which included a considerable number of focal segmental glomerulosclerosis (FSGS) cases.
In general, MMP-11 was commonly expressed in segmental areas of early sclerosis, microadhesions (Figure 1A) as well as in cellular and fibrocellular crescents (Figure 1B, Table 3). All cases of segmental mesangial hyperplasia were also MMP-11 immunopositive. The same degree of MMP-11 positivity was observed at parietal and visceral epithelium, basement membranes of glomerular capillaries (especially in the seven cases of membranous GN) as well as at the mesangium, but no statistically significant differences emerged with regard to the various types of GN (Table 3). Interestingly, biopsy specimens concerning microscopic polyangitis and Wegener's granulomatosis demonstrated identical MMP-11 immunopositive glomerular lesions [i.e. early glomerular injury being characterized by focal segmental fibrinoid necrosis (Figure 1C), while more severe damage was characterized by necrosis and crescent formation often with focal disruption of Bowman's capsule and adjacent periglomerular inflammation]. The tubular pattern of MMP-11 immunopositivity is shown in Figure 1D and the vascular pattern in Figure 1E. With regard to the chronic phase of glomerular injury, fibrotic crescents and totally fibrotic glomeruli were constantly MMP-11 immunonegative.
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When MMP-11 was expressed in glomerular structures, an increased number of CD68-positive cells was more frequently [in detail, 6.69 times more frequently (95% CI = 2.16–20.76)] detected in MMP-11 immunopositive glomeruli than in MMP-11 immunonegative glomeruli (Fischer's exact test, P = 0.001) (Figure 2). No such difference emerged with regard to the presence of Ki67-immunopositive glomerular cells and MMP-11 immunostaining of glomerular structures or lesions (Fisher's exact test, P = 0.17). In the subgroup of secondary GN, the aforementioned difference concerning macrophages, was still of statistical significance (Fisher's exact test, P = 0.016), while this time an additional positive association between MMP-11 and Ki67 interstitial cell immunostaining was detectable (Fisher's exact test, P = 0.017). Of interest, when all hyperplastic GN were examined together as a group, the difference of increased CD68-cell numbers in MMP11-positive glomeruli by comparison to MMP11-negative glomeruli was statistically very strong (Fisher's exact test, P < 0.0001) (Figure 2). As far as Ki67 immunolabelling is concerned, no similar difference could be observed (Fisher's exact test, P = 0.259) (Figure 3). Additionally, it is noteworthy that in the 29 cases of secondary, ANCA-positive GN, the increased number of extraglomerular (interstitial) macrophages appeared to be in parallel with MMP-11 immunostaining of interstitial tissues; however, the statistical significance of this observation could not be validated due to the limited sample size.
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Apart from the glomeruli, MMP-11 was frequently expressed in proximal tubules, in interstitial tissues as well as within interstitial vessels (of arterioles and arteries of small or medium size); the latter expression being predominant in cases of vasculitis (Figure 1E). The aforementioned vessels did not demonstrate fibrinoid necrosis or inflammatory infiltrations. The MMP-11 immunopositivity status of the interstitial fibrosis (of mild to moderate degree) and of the distal tubules was significantly more frequent in the group of the vasculitis-associated GN by comparison to the rest of the secondary GNs examined (P = 0.022 and 0.039, respectively, Figure 4). Similar differences were observed between the aforementioned groups with regard to the MMP-11 immunopositivity status of extraglomerular vessels and of microadhesions, but were of borderline statistical significance (P = 0.055 and 0.063, respectively). Expectedly, increased numbers of interstitial macrophages were detectable in vasculitis-associated GN; these macrophages were frequently Ki67 immunopositive, as aforementioned.
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No statistical correlation appeared to exist between the extent of MMP-11 positivity and histological severity of the respective types of GN within subgroups (Table 3); MMP-11 immunopositivity status was unrelated to patients’ clinical data (Table 4)
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Discussion |
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Human glomerular mesangial cells are embedded in the mesangial matrix and control its turnover through a dynamic equilibrium between synthesis and degradation [12]; the imbalance between degradation and synthesis of ECM causes glomerular sclerosis in various types of GN [13]. MMPs are zinc- and calcium-dependent enzymes that digest ECMs; among them, stromelysins resorb collagens IV, IX and X, fibronectin and laminin [1]. Collagen type IV is a normal component of the mesangial matrix and increases with the expansion of the mesangial matrix in focal glomerular sclerosis [1]. In detail, in FSGS, the affected lobule is often adjacent to Bowman's capsule, the glomerular scars are caused by a combination of collapse of the capillaries and excess production of mesangial matrix. The increased matrix (sclerosis) seen in microadhesions is composed of type IV collagen and laminin. Interestingly, in the examined GN cases, MMP-11 was found to be mainly expressed in segmental areas of early sclerosis and microadhesions, when such lesions were detected. At first sight, when considering the antifibrotic activity of MMPs, our observation may seem paradoxical. However, we should point out that within the MMP family, MMP-11 is an unusual member, because its mature form is unable to hydrolyse the major components of the ECM [11]; only a fragment containing the MMP-11 catalytic domain is known to acquire some enzymatic activity against laminin and type IV collagen in mouse and can thus act as a weak MMP. In any case, the inability of MMP-11 mature form to degrade ECM components casts doubts on whether MMP-11 functions in vivo as a protease [14]. On the other hand, we should take into account that excess matrix, apart from a failure of proteolytic activity, can be the result of excessive activity of local tissue protease inhibitors (TIMPs) [1]; the latter are therefore worth investigating in parallel with MMPs. It is noteworthy that MMP-2 along with TIMP-1 has been reported to be increased in patients with membranous nephropathy in which the thickening of basement membranes is characteristic [3]. Among the various GN groups of our study, MMP-11 was more frequently detected in secondary GNs, especially in those with ANCA-positive, small vessel vasculitis. Since the latter samples are known to have increased numbers of macrophages, MMP-11 may be involved as macrophage product/inflammatory mediator in the pathogenesis of this specific subgroup of GN; a marked activation of acute inflammatory mediator systems at the sites of vascular injury is known to be involved in the pathogenesis of these lesions [15]. This finding is reinforced by experimental models in which rat mesangial cells co-cultured with control macrophages have shown abundant expression of activation markers, including stromelysin [16]. Transfer of NR 8383 macrophages into normal rats induced stromelysin production by resident glomerular cells and this effect was dependent upon macrophage activation [7]. The association between MMP-11 expression and early segmental sclerosis and the statistically significant association between MMP-11 glomerular staining and increased number of intraglomerular macrophages may be connected by the MMP-11 function as a chemotactic inflammatory mediator, leading to the persistent accumulation of macrophages in the mesangium. It has been discovered that an intracellular splicing variant of MMP-11 (ß-stromelysin 3), lacking 32aa at the N-terminal, is directly translated as an active enzyme and is produced by both macrophages and fibroblasts [17]. Therefore, the expression of MMP-11 in macrophages needs to be differentiated from the respective expression in fibroblasts/myofibroblasts before the hypothesis about the action of MMP-11 as a macrophage chemotactic factor is raised. In the immunostained slides of the present study, we were able to get an idea whether MMP-11 immunoreactive cells corresponded to CD68-positive cells by image analysis.
The accumulation of macrophages in the mesangium has already been reported to induce early glomerular sclerosis [17,18]. In detail, irradiation-induced depletion has identified a role for macrophages promoting mesangial hypercellularity and mesangial matrix expansion in the rat remnant kindey [7]. Macrophage depletion in anti-Thy-1 mesangioproliferative nephritis also reduced mesangial matrix expansion (although proteinuria and mesangial cell proliferation was unaffected) [7]. Based on our findings, MMP-11 is likely to be involved in the ECM remodelling taking place in the early phase of fibrosis only through its association with the accumulation of macrophages; in advanced fibrosis, it appears to have no contribution at all, as the MMP-11 immunonegativity of totally fibrotic crescents and glomeruli indicates. With regard to the interstitium, in secondary GNs (especially in vasculitis-associated ones), MMP-11 was more frequently expressed in mild to moderate interstitial fibrosis; this observation is again probably related to the increased number of macrophages, more often detected in the interstitium of vasculitis-associated specimens. We should bare in mind that interstitial fibrosis occurs when there is an imbalance between interstitial matrix production and degradation and is similar in many respects to the same process in glomeruli.
Apart from their potential chemotactic action, MMPs are generally considered capable of stimulating cell proliferation [19] and, as a consequence, mesangial cell proliferation has been effectively suppressed by MMP inhibitors [6]. It is accepted that MMP-11 has low expression in normal adult tissues, whereas it has been found increased in a variety of pathological conditions, such as wound healing, atherosclerotic lesions, rheumatoid arthritis and tumours. It is also highly expressed during development [5], where it seems to be associated to apoptosis, more than to proliferation. On the other hand, it has been reported that MMP-11 may regulate bioavailability of insulin-like growth factor I, favouring cell survival and proliferation [11]. Apart from their mitogenic role, growth factors among which the epidermal growth factor, have been reported to be correlated with a disturbed ECM production resulting in the formation of early sclerotic lesions [20]. MMP-11 can be induced by transforming growth factor-ß (TGF-ß) [21] which is generally considered to exert positive effects on the accumulation of ECMs [22]. Interestingly, like MMP-11, the brightest immunostaining for TGF-ß has been reported in areas of segmental sclerosis [1]. The role of many MMPs indeed appears to be multifactorial and includes mitogenic effects. Persistent mesangial cell proliferation is considered an important precursor of matrix increase and therefore may predispose to scarring [1]. The above data prompted us to examine whether MMP-11 immunoreaction is somehow associated with the number of Ki67-immunopositive cells (a reliable marker of cell proliferation). The lack of correlation between MMP-11 and Ki67 immunoexpression in our samples permits us to consider that this MMP does not generally seem to be related to the proliferation of mesangial cells, despite the fact that MMP-11 was detected in the cytoplasm of mesangial cells in areas of segmental hyperplasia. In cellular and fibrocellular crescents which are hyperplastic lesions being composed mainly of epithelial cells (showing upregulated adhesion molecules expression [23]) but also of macrophages, MMP-11 expression was prominent. Based on the lack of correlation between MMP-11 and Ki67 glomerular immunostaining, MMP-11 is not likely to exert any mitogenic influence in cells forming hyperplastic mesangial lesions as well as cellular crescents but may act as a chemoattractant for macrophages (as the positive association between MMP-11 and CD68-positive cells permits us to speculate). The potential association between MMP-11 and the apoptotic phenomenon is also worth investigating.
In secondary GNs, cell proliferation marker Ki67 was detected in the many interstitial macrophages of the above samples and a positive association emerged between MMP-11 and Ki67 expression in the tubulointerstitium. Since, at least in vasculitis-associated GN, large numbers of macrophages were expectedly encountered in the interstitial tissue, the aforementioned relationship might be justified by the increased number of interstitial proliferating macrophages known to exist in such cases [15,24]; in fact, it has been demonstrated that production of various molecules by the macrophages [such as macrophage colony-stimulating factor (M-CSF)] is responsible for local macrophage proliferation in human GN [9]. Like M-CSF, MMP-11 might thus exert a different role in macrophages of the interstitium, especially in vasculitis-associated GN, than in intraglomerular macrophages. As far as the tubular expression of MMP-11 in our specimens is concerned, the distal tubules which expressed MMP-11 quite often in our study, are known to express 
2ß1-integrin, which happens to be a receptor for collagen and laminin, and thus appear to contribute to the creation of interstitial matrix [1]. Furthermore, tubular epithelial cells are considered a major site of molecule production, possibly including MMP-11, in the injured kidney; these molecules have a proven role in promoting interstitial macrophage infiltration and tubulointerstitial damage [25].
In conclusion, MMP-11 as a potential inflammatory mediator may exert a chemotactic influence on macrophages which aggregate in the mesangium, induce early fibrosis and which are partially involved in the formation of cellular and fibrocellular crescents. MMP-11 appears to have neither antifibrotic nor mitogenic effect within the glomeruli. Since our descriptive data cannot support conclusions regarding function, the simultaneous investigation of matrix proteins and local tissue protease inhibitors is necessary so that more light is shed on MMP-11 role in glomerular disease.
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Acknowledgement |
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The authors appreciate the excellent technical assistance of Miss Effie Panayotopoulou, Biologist and the skillful discussions of Dr Thomas Papathomas.
Conflict of interest statement. None declared.
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Accepted in revised form: 26. 8.06
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