Abstract
Over the last years, evidence emerged demonstrating that the progression of renal fibrosis is reversible in experimental models. The present review summarizes the new insights concerning the mechanisms of progression and regression of renal disease and examines this novel evidence under the light of feasibility and transfer to human nephropathies. The involved mechanisms are discussed with particular emphasis on the fibrotic role of vasoactive peptides such as angiotensin II and endothelin, and growth factors such as transforming growth factor β (TGFβ). The possibility of regression is introduced by presenting the in vivo efficiency of anti-hypertensive treatments and of systems that antagonize the fibrogenic action of TGFβ such as bone morphogenic protein-7 (BMP-7) and hepatocyte growth factor. Finally, we provide a brief description of the promising future directions and clinical considerations about the applications of the experimental data to humans.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- BMP-7:
-
bone morphogenic protein
- DSS:
-
dahl salt-sensitive
- EGF:
-
epidermal growth factor
- ESRD:
-
end-stage renal disease
- HGF:
-
hepatocyte growth factor
- PAI-1:
-
plasminogen activator inhibitor-1
- PDGF:
-
platelet-derived growth factor
- TGFβ:
-
transforming growth factor β
References
Incidence and prevalence of ESRD##United States Renal Data System. Am J Kidney Dis 1998; 32 (Suppl 1): S38–S49.
Valderrabano F, Berthoux FC, Jones EH et al. Report on management of renal failure in Europe, XXV, 1994 end stage renal disease and dialysis report. The EDTA-ERA Registry. Nephrol Dial Transplant 1996; 11 (Suppl 1): 2–21.
Chatziantoniou C, Boffa JJ, Ardaillou R, Dussaule JC . Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice: role of endothelin. J Clin Invest 1998; 101: 2780–2789.
Boffa JJ, Tharaux PL, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C . II activates collagen type I gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis: evidence for an endothelin-mediated mechanism. Circulation 1999; 100: 1901–1908.
Tharaux PL, Chatziantoniou C, Fakhouri F, Dussaule JC . Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension 2000; 36: 330–336.
Flamant M, Tharaux PL, Placier S, Henrion D, Coffman T, Chatziantoniou C et al. Epidermal growth factor transactivation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice. FASEB J 2003; 17: 327–329.
Fakhouri F, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C . Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta. J Am Soc Nephrol 2001; 12: 2701–2710.
Berk BC . Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J Am Soc Nephrol 1999; 10 (Suppl 11): S62–S68.
Fogo AB . Renal fibrosis and the renin-angiotensin system. AAdv Nephrol Necker Hosp 2001; 31: 69–87.
Klahr S, Morrissey JJ . The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. Kidney Int Suppl 2000; 75: S7–S14.
Ruiz-Ortega M, Esteban V, Ruperez M, Sanchez-Lopez E, Rodriguez-Vita J, Carvajal G et al. Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens 2006; 15: 159–166.
Modlinger PS Wilcox CS Aslam S . Nitric oxide, oxidative stress, and progression of chronic renal failure. Semin Nephrol 2004; 24: 354–365.
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354: 447–455.
Yusuf S, Sleight P, Poque J, Bosch J, Dussaule JC, Dagenais G et al. Vitamin E supplementation and cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 154–160.
Aslam, Santha T, Leone A, Wilcox C . Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis. Kidney Int 2006; 70: 2109–2115.
Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The angiotensin-converting-enzyme inhibition in progressive renal insufficiency study group. N Engl J Med 1996; 334: 939–945.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869.
Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P . The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–878.
Boffa JJ, Ying L, Placier S, Stefanski A, Dussaule JC, Chatziantoniou C . Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and metalloproteinases. J Am Soc Nephrol 2003; 14: 1132–1144.
Adamczak M, Gross ML, Amann K, Ritz E . Reversal of glomerular lesions involves coordinated restructuring of glomerular microvasculature. J Am Soc Nephrol 2004; 15: 3063–3072.
Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K et al. Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol 2003; 14: 2833–2842.
Eddy A, Giachelli CM . Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int 1995; 47: 1546–1557.
Ma LJ, Nakamura S, Whitsitt JS, Marcantoni C, Davidson JM, Fogo AB . Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1. Kidney Int 2000; 58: 2425–2436.
Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE . Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation 2001; 104: 839–844.
Oda T, Jung YO, Kim HS, Cai X, Lopez-Guisa JM, Ikeda Y et al. PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 2001; 60: 587–596.
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.
Hertig A, Berrou J, Allory Y, Breton L, Commo F, Costa De Beaureqard MA 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.
Benigni A, Zoja C, Corna D, Orisio S, Facchinetti D, Benati L et al. Blocking both type A and B endothelin receptors in the kidney attenuates renal injury and prolongs survival in rats with remnant kidney. Am J Kidney Dis 1996; 27: 416–423.
Hocher B, Thöne-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V et al. Endothelin-1 transgenic mice develops glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 1997; 99: 1380–1389.
Boffa JJ Tharaux PL, Dussaule JC, Chatziantoniou C . Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension 2001; 37: 490–496.
Ostendorf T Kunter U, Grone HJ, Bahlmann F, Kawachi H, Shimizu F et al. Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 2001; 12: 909–918.
François H, Placier S, Flamant M, Tharaux PL, Chansel D, Dussaule JC et al. Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition. FASEB J 2004; 18: 926–929.
Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA 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.
Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R . BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964–968.
Liu Y, Yang J . Hepatocyte growth factor: new arsenal in the fights against renal fibrosis? Kidney Int 2006; 70: 238–240.
Yang J, Dai C, Liu Y . Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction. Am J Pathol 2003; 163: 621–632.
Yang J, Liu Y . Delayed administration of hepatocyte growth factor reduces renal fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol 2003; 284: F349–F357.
Herrero-Fresnada, Torras J, Franquesa M, Vidal A, Cruzado JM, Lloberas N et al. HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms. Kidney Int 2006; 70: 265–274.
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.
Cheng S, Lovett DH, Gelatinase A . (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol 2003; 162: 1937–1949.
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, (E-pub 2006 August 4).
Zeisberg M, Khurana M, Rao VH, Cosgrove D, Rougier JP, Werner MC et al. Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med 2006; 3: e100.
Vogel W, Gish GD, Alves F, Pawson T . The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997; 1: 13–23.
Matsuyama W, Faure M, Yoshimura T . Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade. J Immunol 2003; 171: 3520–3532.
Matsuyama W, Kamohara H, Galligan C, Faure M, Yoshimura T . Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. FASEB J 2003; 17: 1286–1288.
Flamant J, Placier S, Rodenas A, Curat CA, Vogel WF, Chatziantoniou C et al. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J Am Soc Nephrol 2006; 17: 3374–3381.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by P Nicotera
Rights and permissions
About this article
Cite this article
Dussaule, JC., Chatziantoniou, C. Reversal of renal disease: is it enough to inhibit the action of angiotensin II?. Cell Death Differ 14, 1343–1349 (2007). https://doi.org/10.1038/sj.cdd.4402143
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4402143
Keywords
This article is cited by
-
Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice
Kidney International (2014)
-
Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury
Laboratory Investigation (2010)
-
Reversal of proteinuric renal disease and the emerging role of endothelin
Nature Clinical Practice Nephrology (2008)
-
Janus a god with two faces: death and survival utilise same mechanisms conserved by evolution
Cell Death & Differentiation (2007)
-
Pathobiology of transforming growth factor β in cancer, fibrosis and immunologic disease, and therapeutic considerations
Laboratory Investigation (2007)
