Nephrology Dialysis Transplantation

NDT Advance Access originally published online on November 9, 2005
Nephrology Dialysis Transplantation 2006 21(1):16-20; doi:10.1093/ndt/gfi265

This Article Abstract FREE Full Text (PDF) All Versions of this Article: 21/1/16    most recent gfi265v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (38) Request Permissions Disclaimer Google Scholar Articles by Ruiz-Ortega, M. Articles by Egido, J. Search for Related Content PubMed PubMed Citation Articles by Ruiz-Ortega, M. Articles by Egido, J. Social Bookmarking          What's this?

© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

---

Editorial Comment

Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases

Marta Ruiz-Ortega, Mónica Rupérez, Vanesa Esteban, Juan Rodríguez-Vita, Elsa Sánchez-López, Giselle Carvajal and Jesús Egido

Vascular and Renal Research Laboratory, Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain

Correspondence and offprint requests to: Marta Ruiz-Ortega, Vascular and Renal Research Laboratory, Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain. Email: mruizo{at}fjd.es

	Abstract

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
Angiotensin II (AngII) participates in the pathogenesis of renal diseases, through the regulation of two key processes inflammation and fibrosis. AT₁ and AT₂ are the main receptors of AngII. AT₁ mediates most of the actions of AngII. This receptor regulates the expression of profibrotic factors, such as connective tissue growth factor (CTGF). The Smad signalling pathway and the Rho/Rho kinase system are two novel mechanisms involved in AngII-induced matrix regulation recently described. The role of AT₂ receptors in renal pathophysiological processes is not fully elucidated. Experimental data suggest that AT₂ receptors through activation of nuclear factor-B participate in renal inflammatory cell recruitment. Studies in animal models of kidney injury have shown that the combined blockade of both AT₁ and AT₂ receptors, as well as the inhibition of the NF-B pathway are necessary to stop the inflammatory process fully. On the whole, these data highlight the complex signalling systems activated by AngII and suggest novel potential targets to block fibrosis and inflammation in renal diseases.

Keywords: angiotensin II; fibrosis; inflammation; proinflammatory cytokines; growth factors

	Introduction

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
Angiotensin II (AngII), the main peptide of the renin–angiotensin system (RAS), is involved in the pathogenesis of renal diseases [1,2]. This peptide acts through its binding to two specific receptors, AT₁ and AT₂ [2]. AT₁ is responsible for most of the pathophysiological actions of AngII. By promoting proliferation, inflammation and fibrosis, AngII contributes to chronic diseases, such as hypertension, atherosclerosis, cardiac hypertrophy and renal injury, The role of the AT₂ receptor is not completely defined. AT₂ is involved in cell growth inhibition and inflammatory cell recruitment in the kidney [2–4]. We will review here the information regarding the novel mechanisms involved in the fibrotic and inflammatory response caused by AngII.

	AngII regulates fibrosis via the AT1 receptor: role of CTGF and the Smad signalling pathway

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
AngII via AT₁ regulates extracellular matrix (ECM) accumulation mediated by the endogenous production of profibrotic growth factors, such as transforming growth factor-ß (TGF-ß). Angiotensin-converting enzyme (ACE) inhibitors and AT₁ antagonists decrease tissue expression of TGF-ß and fibrosis; furthermore, blockade of TGF-ß diminishes AngII-induced ECM production [2,3]. Although TGF-ß is one of the main regulators of fibrosis, therapeutic strategies blocking TGF-ß actions have not afforded the expected beneficial effects probably because of its anti-inflammatory properties [5]. This is one of the reasons why novel antifibrotic targets are under active investigation. Connective tissue growth factor (CTGF) is a novel profibrotic factor that is upregulated in different human kidney diseases and contributes to renal fibrosis and tubuloepithelial transdifferentiation [6]. In models of renal injury, ACE inhibitors and AT₁ antagonists diminished CTGF upregulation and fibrosis [7,8]. We have also demonstrated that the blockade of CTGF, by an antisense CTGF oligonucleotide, diminished AngII-induced fibrosis, shown by diminution of fibronectin production [7,9]. These results suggest that CTGF could be a novel antifibrotic target (Figure 1).

View larger version (38K): [in this window] [in a new window]   Fig. 1. Potential novel therapeutic strategies to block AngII-induced fibrosis. AngII via AT1 activates the Smad signalling system and the Rho/Rho kinase pathway that upregulates CTGF production and fibrosis.

 
The Smad proteins are essential components of the intracellular signalling pathways, acting as transcription factors of TGF-ß-mediated responses, including fibrosis [10]. We have recently shown that AngII via AT₁ activates the Smad signalling system, independently of TGF-ß [11]. In vascular smooth muscle cells (VSMCs), AngII caused a rapid and direct activation of Smad2 phosphorylation, nuclear translocation of phosphorylated Smad2 and Smad4, increased DNA-binding activity and Smad-dependent gene transcription. In AngII-infused rats, aortic Smad overexpression was associated with CTGF induction and occurred before ECM accumulation [11]. Smad7 may function as a general negative regulator of TGF-ß receptor signalling [12]. Transient transfection with Smad7, which interferes with receptor-mediated activation of Smad2 and Smad3, diminished CTGF, fibronectin and type 1 procollagen upregulation caused by AngII [11]. Moreover, Smad7 overexpression blocks TGF-ß-induced ECM production and renal fibrosis [13–15]. AT₁ blockade diminishes Smad pathway activation and fibrosis in the model of renal injury caused by unilateral ureteral obstruction (UUO), in myocardial infarction in rats and in the aorta of AngII-infused rats [11,16,17]. These data indicate that Smad signalling could be a common mechanism of AngII-mediated fibrosis in cardiovascular and renal diseases and that the blockade of Smad activation could be another important anti-fibrotic target (Figure 1).

	The small G protein Rho and AngII responses

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
The AT₁ are G-coupled receptors and activate small G proteins, including RhoA and the Rho kinase system [18]. The Rho/Rho kinase signalling pathway participates in the development of fibrotic lesions in several tissues including the kidney. In different experimental models, such as hypertensive glomerulosclerosis, UUO, nephrectomized spontaneously hypertensive rats and L-NAME-treated rats, administration of Rho kinase inhibitors diminished glomerular and tubulointerstitial injury, inflammation and fibrosis, and downregulated smooth muscle -actin gene overexpression, as well as the TGF-ß and ECM proteins [19–24]. In rats infused with AngII, we have shown that the Rho kinase inhibitor Y-27632 diminished tubular damage, the number of inflammatory cells, and renal overexpression of CTGF and proinflammatory parameters [25]. All these data suggest that Rho kinase inhibitors could be novel targets for renal therapy (Figure 1).

	AngII and the inflammatory response: role of AngII receptors and the NF-B pathway

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
AngII contributes to the recruitment of infiltrating cells into the kidney; AngII causes the adhesion of circulating cells to endothelial and mesangial cells, and the migration of inflammatory cells into the kidney. This process is mediated by upregulation of adhesion molecules, cytokines and chemokines [1].

ACE inhibitors have been shown to diminish inflammatory cell infiltration and inflammatory markers in many animal models of renal injury [1]. AngII via AT₁ receptors upregulates many proinflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), through the activation of several intracellular signalling systems, including the nuclear factor-B (NF-B), mitogen-activated protein kinase (MAPK) cascade, Rho proteins and redox pathways [1]. Some experimental data suggest that AT₂ receptors are involved in the inflammatory cell recruitment in the kidney. Only AT₂, but not AT₁, antagonists diminished the number of inflammatory cells in different animal models, including systemic infusion of AngII and UUO [3,4,8,26,27]. We have recently demonstrated that combined treatment with AT₁ and AT₂ antagonists blocked the inflammatory response, and lowered the number of infiltrating cells and the overexpression of proinflammatory genes to control levels in those models [8,27]. In the UUO model, AT₂ blockade diminished tumour necrosis factor- (TNF-) and RANTES overexpression, and the simultaneous blockade of both receptors abolished MCP-1 gene upregulation [8]. NF-B activation has been described in kidney diseases [1]. In vivo, AngII activates the renal NF-B pathway that was partially diminished by AT₁ or AT₂ antagonists alone, and was abolished by combination of both receptor antagonists or ACE inhibition [4,8,27]. In mesangial cells, NF-B activation was mediated by both AT₁ and AT₂ receptors [4]; in tubuloepithelial cells, this was mainly by AT₁ [4], while in endothelial cells it was via AT₂ [28]. In the UUO model, we have found that blockade of renal NF-B activation by treatment with two different NF-B inhibitors, pyrrolidine dithiocarbamate (PDTC) and parthenolide, diminished the inflammatory cell infiltration and downregulated gene expression of several proinflammatory factors [8]. In spontaneously hypertensive rats, NF-B inhibition attenuated renal interstitial inflammation and hypertension [29]. These data suggest that in some experimental renal diseases, the blockade of AngII generation by an ACE inhibitor or by combined blockade of both AT₁ and AT₂ receptors, as well as by the inhibition of the NF-B pathway, is necessary to stop the inflammatory process fully (Figure 2).

View larger version (46K): [in this window] [in a new window]   Fig. 2. Effect of pharmacological blockade of the renin–angiotensin system in renal inflammation. The blockade of both AT1 and AT2 receptors, or ACE inhibition as well as the inhibition of the NF-B pathway block the inflammatory response through the regulation of NF-B and proinflammatory genes.

 
In human kidney diseases, the activated renal renin–angiotensin system has been described. In diabetic nephropathy, elevated AngII generation did correlate with the presence of inflammatory cell infiltration, the activation of NF-B and proinflammatory gene overexpression [30]. These observations emphasize the importance of treatments that block the AngII-induced inflammatory process in human renal diseases.

	Conclusion

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 
Drugs that modulate the renin–angiotensin system, such as ACE inhibitors and AT₁ antagonists, have demonstrated protective renal effects and can ameliorate fibrosis. Current strategies in clinical practice combine treatments with ACE inhibitors and AT₁ blockers, due to their potential additive beneficial effects [31]. However, these treatments did not cause regression of renal damage, suggesting that novel approaches are needed. The data presented here highlight potential interesting candidates for antifibrotic treatments, including CTGF, the Smad signalling system and the Rho/Rho kinase pathway. Future studies are necessary to evaluate their potential beneficial effects fully in kidney diseases.

The Ang receptor subtype, AT₁ or AT₂, involved in the inflammatory response in the kidney is not completely elucidated. Our results show that the blockade of both AT₁ and AT₂ receptors is necessary to stop the inflammatory process completely, at least in experimental models. The inhibition of the NF-B pathway also prevents inflammation and experimental renal damage. All these experimental studies provide a rationale to investigate further the involvement of the AT₂/NF-B pathway in the inflammatory response in kidney diseases. These results could have potential clinical consequences in the treatment of severe human nephritis.

	Acknowledgments

 
The study was supported by grants from FIS (PI0205513, PI020822), Comunidad Madrid (CAM: GR/SAL/0411/2004), SAF (2004-06109), Fundación Mutua Madrileña, Sociedad Española de Cardiología and Red Cardiovascular Española (RECAVA: 03.01). M.R., E. S.-L., V.E., and J. R.-V. are fellows of FIS. G.C. is a fellow of the Fundación Carolina.

	References

Top Abstract Introduction AngII regulates fibrosis via... The small G protein... AngII and the inflammatory... Conclusion References

 

1. Ruiz-Ortega M, Lorenzo O, Suzuki Y et al. Proinflammatory actions of angiotensin II. Curr Opin Nephrol Hypertens 2001; 10: 321–329[CrossRef][ISI][Medline]
2. Ruiz-Ortega M, Ruperez M, Esteban V, Egido J. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep 2003; 5: 73–79[ISI][Medline]
3. Wolf G, Ziyadeh FN, Thaiss F et al. Angiontensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest 1997; 100: 1047–1058[ISI][Medline]
4. Ruiz-Ortega M, Lorenzo O, Ruperez M et al. Systemic infusion of angiotensin II into normal rats activates nuclear factor -B and AP-1 in the kidney. Role of AT1 and AT2 receptors. Am J Pathol 2001; 158: 1743–1756[Abstract/Free Full Text]
5. Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol 2004; 24: 399–404[Abstract/Free Full Text]
6. Perbal B. CCN proteins: multifunctional signalling regulators. Lancet 2004; 363: 62–64[CrossRef][ISI][Medline]
7. Ruperez M, Lorenzo O, Blanco-Colio LM et al. The connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation 2003; 108: 1499–1509[Abstract/Free Full Text]
8. Esteban V, Lorenzo O, Ruperez M et al. Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol. 2004; 15: 1514–1529[Abstract/Free Full Text]
9. Ruperez M, Ruiz-Ortega M, Esteban V et al. Angiotensin II increases connective tissue growth factor in the kidney. Am J Pathol 2003; 163: 1937–1947[Abstract/Free Full Text]
10. Massague J, Chen YG. Controlling TGF-signaling. Genes Dev 2000; 4: 627–644
11. Rodriguez-Vita J, Sanchez-Lopez E, Esteban V, Ruperez M, Egido J, Ruiz-Ortega M. Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism. Circulation 2005; 111: 2509–2517[Abstract/Free Full Text]
12. Nakao A, Okumura K, Ogawa H. Smad7: a new key player in TGF-beta-associated disease. Trends Mol Med 2002; 8: 361–363[CrossRef][ISI][Medline]
13. Li JH, Zhu HJ, Huang XR et al. Smad7 inhibits fibrotic effect of TGF-beta on renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol 2002; 13: 1464–1472[Abstract/Free Full Text]
14. 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]
15. Chen R, Huang C, Morinelli TA, Trojanowska M, Paul RV. Blockade of the effects of TGF-beta1 on mesangial cells by overexpression of Smad7. J Am Soc Nephrol 2002; 13: 887–893[Abstract/Free Full Text]
16. Hao J, Wang B, Jones SC, Jassal DS, Dixon IM. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol 2000; 279: H3020–H3030[ISI]
17. Wamsley-Davis A, Padda R, Truong LD et al. AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using Candesartan. Am J Physiol 2004; 287: F474–F480
18. Yamakawa T, Tanaka S, Numaguchi K et al. Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension 2000; 35: 313–318[Abstract/Free Full Text]
19. 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][ISI][Medline]
20. Kanda T, Wakino S, Hayashi K et al. Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kidney Int 2003; 64: 2009–2019[CrossRef][ISI][Medline]
21. Satoh S, Yamaguchi T, Hitomi A et al. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol 2002; 455: 169–114[CrossRef][ISI][Medline]
22. Teraishi K, Kurata H, Nakajima A et al. Preventive effect of Y-27632, a selective Rho-kinase inhibitor, on ischemia/reperfusion-induced acute renal failure in rats. Eur J Pharmacol 2004; 505: 205–211[CrossRef][ISI][Medline]
23. Nishikimi T, Akimoto K, Wang X et al. Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. Hypertensenion 2004; 22: 1787–1796
24. Kataoka C, Egashira K, Inoue S et al. Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 2002; 39: 245–250[Abstract/Free Full Text]
25. Rupérez M, Sánchez-López E, Blanco-Colio LM et al. The Rho-kinase pathway regulates AngII-induced renal damage Kidney Int 2005; 68 [Supp 99]
26. Morrissey JJ, Klahr S. Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis. Am J Physiol 1998; 274: F580–F586
27. Esteban V, Ruperez M, Vita JR et al. Effect of simultaneous blockade of AT1 and AT2 receptors on the NFkappaB pathway and renal inflammatory response. Kidney Int 2003; 86: S33–S38
28. Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F. Angiotensin II activates nuclear transcription factor-B through AT1 and AT2 receptors. Kidney Int 2002; 61: 1986–1995[CrossRef][ISI][Medline]
29. Rodriguez-Iturbe B, Ferrebuz A, Varegas V et al. Early and sustained inhibition of nuclear factor kappa B prevents hypertension in spontaneously hypertensive rats. J Pharmacol Exp Ther 2005; 315: 51–77[Abstract/Free Full Text]
30. Mezzano S, Aros C, Droguett A et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 2004; 19: 2505–2512[Abstract/Free Full Text]
31. 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][ISI][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				E. I. Ager, J. Neo, and C. Christophi The renin-angiotensin system and malignancy Carcinogenesis, September 1, 2008; 29(9): 1675 - 1684. [Abstract] [Full Text] [PDF]

				K. Block, A. Eid, K. K. Griendling, D.-Y. Lee, Y. Wittrant, and Y. Gorin Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II: ROLE IN MESANGIAL CELL HYPERTROPHY AND FIBRONECTIN EXPRESSION J. Biol. Chem., August 29, 2008; 283(35): 24061 - 24076. [Abstract] [Full Text] [PDF]

				T.-D. Liao, X.-P. Yang, Y.-H. Liu, E. G. Shesely, M. A. Cavasin, W. A. Kuziel, P. J. Pagano, and O. A. Carretero Role of Inflammation in the Development of Renal Damage and Dysfunction in Angiotensin II-Induced Hypertension Hypertension, August 1, 2008; 52(2): 256 - 263. [Abstract] [Full Text] [PDF]

				J. L. Cook, R. N. Re, D. L. deHaro, J. M. Abadie, M. Peters, and J. Alam The Trafficking Protein GABARAP Binds to and Enhances Plasma Membrane Expression and Function of the Angiotensin II Type 1 Receptor Circ. Res., June 20, 2008; 102(12): 1539 - 1547. [Abstract] [Full Text] [PDF]

				I. Hamming, H. van Goor, A. J. Turner, C. A. Rushworth, A. A. Michaud, P. Corvol, and G. Navis Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats Exp Physiol, May 1, 2008; 93(5): 631 - 638. [Abstract] [Full Text] [PDF]

				T. Kisseleva and D. A. Brenner Fibrogenesis of Parenchymal Organs Proceedings of the ATS, April 15, 2008; 5(3): 338 - 342. [Abstract] [Full Text] [PDF]

				T. Kisseleva and D. A. Brenner Mechanisms of Fibrogenesis Experimental Biology and Medicine, February 1, 2008; 233(2): 109 - 122. [Abstract] [Full Text] [PDF]

				E. Sanchez-Lopez, J. Rodriguez-Vita, C. Cartier, M. Ruperez, V. Esteban, G. Carvajal, R. Rodrigues-Diez, J. J. Plaza, J. Egido, and M. Ruiz-Ortega Inhibitory effect of interleukin-1 on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells Am J Physiol Renal Physiol, January 1, 2008; 294(1): F149 - F160. [Abstract] [Full Text] [PDF]

				M. Konigshoff, A. Wilhelm, A. Jahn, D. Sedding, O. V. Amarie, B. Eul, W. Seeger, L. Fink, A. Gunther, O. Eickelberg, et al. The Angiotensin II Receptor 2 Is Expressed and Mediates Angiotensin II Signaling in Lung Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2007; 37(6): 640 - 650. [Abstract] [Full Text] [PDF]

				S. Gauer, V. Segitz, and M. Goppelt-Struebe Aldosterone induces CTGF in mesangial cells by activation of the glucocorticoid receptor Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3154 - 3159. [Abstract] [Full Text] [PDF]

				P. Chen, A. M. Guo, P. A. Edwards, G. Trick, and A. G. Scicli Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1619 - R1629. [Abstract] [Full Text] [PDF]

				M. J. Socha, M. Manhiani, N. Said, J. D. Imig, and K. Motamed Secreted Protein Acidic and Rich in Cysteine Deficiency Ameliorates Renal Inflammation and Fibrosis in Angiotensin Hypertension Am. J. Pathol., October 1, 2007; 171(4): 1104 - 1112. [Abstract] [Full Text] [PDF]

				S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen Angiotensin-Converting Enzyme and Vascular Remodeling Circ. Res., August 31, 2007; 101(5): 441 - 454. [Abstract] [Full Text] [PDF]

				M. Sakai, K. Tamura, Y. Tsurumi, Y. Tanaka, Y. Koide, M. Matsuda, T. Ishigami, M. Yabana, Y. Tokita, Y. Hiroi, et al. Expression of MAK-V/Hunk in renal distal tubules and its possible involvement in proliferative suppression Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1526 - F1536. [Abstract] [Full Text] [PDF]

				M. Ruiz-Ortega, J. Rodriguez-Vita, E. Sanchez-Lopez, G. Carvajal, and J. Egido TGF-{beta} signaling in vascular fibrosis Cardiovasc Res, May 1, 2007; 74(2): 196 - 206. [Abstract] [Full Text] [PDF]

				J.-K. Park, R. Fischer, R. Dechend, E. Shagdarsuren, A. Gapeljuk, M. Wellner, S. Meiners, P. Gratze, N. Al-Saadi, S. Feldt, et al. p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II-Induced Target Organ Damage Hypertension, March 1, 2007; 49(3): 481 - 489. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) All Versions of this Article: 21/1/16    most recent gfi265v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (38) Request Permissions Disclaimer Google Scholar Articles by Ruiz-Ortega, M. Articles by Egido, J. Search for Related Content PubMed PubMed Citation Articles by Ruiz-Ortega, M. Articles by Egido, J. Social Bookmarking          What's this?

Online ISSN 1460-2385 - Print ISSN 0931-0509

Copyright © 2008 European Renal Association - European Dialysis and Transplant Assoc

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics