Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Potential approaches to reverse or repair renal fibrosis

Nature Reviews Nephrology volume 10, pages 226–237 (2014)Cite this article

Subjects

Key Points

  • On the basis of promising preclinical and clinical data, the fatalistic concept of the 'point of no return' in chronic kidney disease (CKD) must be revised; evidence supports that CKD can be reversed

  • As fibrosis is controlled by overlapping pathways across all organs, the vast pipeline of antifibrotic drugs in preclinical and clinical development might be of benefit to patients with CKD in the future

  • Ongoing clinical trials to ameliorate fibrosis in the kidney are assessing transforming growth factor-β1 inhibitors, connective tissue growth factor inhibitors, bone morphogenic protein-7 agonists and endothelin-1 antagonists

  • Other strategies are exploring blockade of CC chemokine receptor type 2 and phosphodiesterase type 5 inhibition

Abstract

The concept of reversing chronic kidney disease (CKD) has been intensively researched over the past decade. Indeed, as the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. Now, the possibility of effective antifibrotic treatment has been established in experimental models of CKD and multiple antifibrotic compounds—in kidney disease, as well as in fibrotic diseases of the skin, liver and lung—are being assessed in clinical trials. These strategies target various components of the fibrotic pathway, from signalling molecules that include transforming growth factor-β, phosphatidylinositide 3-kinase and chemokines to microRNAs. Here, we discuss therapeutic concepts to inhibit or even reverse chronic kidney injury and review the leading candidate antifibrotic drugs to be introduced to clinical use.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of different antifibrotic strategies.
Figure 2: Agents that target the TGF-β and BMP-7 signalling pathways.

Similar content being viewed by others

References

  1. Ahlmén, J. Incidence of chronic renal insufficiency. A study of the incidence and pattern of renal insufficiency in adults during 1966–1971 in Gothenburg. Acta Med. Scand. Suppl. 582, 1–50 (1975).

    PubMed  Google Scholar 

  2. Rutherford, W. E., Blondin, J., Miller, J. P., Greenwalt, A. S. & Vavra, J. D. Chronic progressive renal disease: rate of change of serum creatinine concentration. Kidney Int. 11, 62–70 (1977).

    CAS  PubMed  Google Scholar 

  3. Leumann, E. P. Progression of renal insufficiency in pediatric patients: estimation from serum creatinine. Helv. Paediatr. Acta 33, 25–35 (1978).

    CAS  PubMed  Google Scholar 

  4. Drawz, P. E., Goswami, P., Azem, R., Babineau, D. C. & Rahman, M. A simple tool to predict end-stage renal disease within 1 year in elderly adults with advanced chronic kidney disease. J. Am. Geriatr. Soc. 61, 762–768 (2013).

    PubMed  PubMed Central  Google Scholar 

  5. McLaughlin, M. J. & Courtney, A. E. Early recognition of CKD can delay progression. Practitioner 257, 13–17 (2013).

    PubMed  Google Scholar 

  6. Whaley-Connell, A. T., Tamura, M. K., Jurkovitz, C. T., Kosiborod, M. & McCullough, P. A. Advances in CKD detection and determination of prognosis: executive summary of the National Kidney Foundation—Kidney Early Evaluation Program (KEEP) 2012 annual data report. Am. J. Kidney Dis. 61, S1–S3 (2013).

    PubMed  PubMed Central  Google Scholar 

  7. Fioretto, P., Steffes, M. W., Sutherland, D. E., Goetz, F. C. & Mauer, M. Reversal of lesions of diabetic nephropathy after pancreas transplantation, N. Engl. J. Med. 339, 69–75 (1998).

    CAS  PubMed  Google Scholar 

  8. Fioretto, P., Sutherland, D. E., Najafian, B. & Mauer, M. Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int. 69, 907–912 (2006).

    CAS  PubMed  Google Scholar 

  9. Remuzzi, A. et al. Regression of diabetic complications by islet transplantation in the rat. Diabetologia 52, 2653–2661 (2009).

    CAS  PubMed  Google Scholar 

  10. Risdon, R. A., Sloper, J. C. & De Wardener, H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2, 363–366 (1968).

    CAS  PubMed  Google Scholar 

  11. Bohle, A., Glomb, D., Grund, K. E. & Mackensen, S. Correlation between relative interstitial volume of the renal cortex and serum creatinine concentration in minimal changes with nephrotic syndrome and in focal sclerosing glomerulonephritis. Virchows Arch. A Pathol. Anat. Histol. 376, 221–232 (1977).

    CAS  PubMed  Google Scholar 

  12. Zeisberg, M. & Kalluri, R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 304, C216–C225 (2013).

    CAS  PubMed  Google Scholar 

  13. Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zeisberg, M. & Neilson, E. G. Mechanisms of tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 21, 1819–1834 (2010).

    CAS  PubMed  Google Scholar 

  15. Aydin, S. et al. Influence of microvascular endothelial cells on transcriptional regulation of proximal tubular epithelial cells. Am. J. Physiol. Cell Physiol. 294, C543–554 (2008).

    CAS  PubMed  Google Scholar 

  16. Eddy, A. A. Molecular insights into renal interstitial fibrosis. J. Am. Soc. Nephrol. 7, 2495–2508 (1996).

    CAS  PubMed  Google Scholar 

  17. Kim, H. et al. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J. Am. Soc. Nephrol. 12, 736–748 (2001).

    CAS  PubMed  Google Scholar 

  18. Yang, J. et al. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J. Clin. Invest. 110, 1525–1538 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zeisberg, M. et al. Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease, PLoS Med. 3, e100 (2006).

    PubMed  PubMed Central  Google Scholar 

  20. Zeisberg, M. et al. BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964–968 (2003).

    CAS  PubMed  Google Scholar 

  21. Zeisberg, M. et al. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am. J. Physiol. Renal Physiol. 285, F1060–F1067 (2003).

    CAS  PubMed  Google Scholar 

  22. Iredale, J. P. et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 102, 538–549 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fallowfield, J. A. & Iredale, J. P. Reversal of liver fibrosis and cirrhosis—an emerging reality. Scott. Med. J. 49, 3–6 (2004).

    CAS  PubMed  Google Scholar 

  24. Schuppan, D., Ruehl, M., Somasundaram, R. & Hahn, E. G. Matrix as a modulator of hepatic fibrogenesis, Semin. Liver Dis. 21, 351–372 (2001).

    CAS  PubMed  Google Scholar 

  25. Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

    CAS  PubMed  Google Scholar 

  26. Zeisberg, M., Strutz, F. & Müller, G. A. Role of fibroblast activation in inducing interstitial fibrosis. J. Nephrol. 13 (Suppl. 3), S111–S120 (2000).

    PubMed  Google Scholar 

  27. Harris, R. C. & Neilson, E. G. Toward a unified theory of renal progression. Annu. Rev. Med. 57, 365–380 (2006).

    CAS  PubMed  Google Scholar 

  28. Rodemann, H. P. & Müller, G. A. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am. J. Kidney Dis. 17, 684–686 (1991).

    CAS  PubMed  Google Scholar 

  29. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544–550 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zeisberg, E. M., Potenta, S. E., Sugimoto, H., Zeisberg, M. & Kalluri, R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J. Am. Soc. Nephrol. 19, 2282–2287 (2008).

    PubMed  PubMed Central  Google Scholar 

  34. Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

    CAS  PubMed  Google Scholar 

  35. Richeldi, L. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 365, 1079–1087 (2011).

    CAS  PubMed  Google Scholar 

  36. Frazier, K., Williams, S., Kothapalli, D., Klapper, H. & Grotendorst, G. R. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J. Invest. Dermatol. 107, 404–411 (1996).

    CAS  PubMed  Google Scholar 

  37. Igarashi, A. et al. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J. Invest. Dermatol. 106, 729–733 (1996).

    CAS  PubMed  Google Scholar 

  38. Iwano, M. et al. Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol. Ther. 3, 149–159 (2001).

    CAS  PubMed  Google Scholar 

  39. Hodgkins, K. S. & Schnaper, H. W. Tubulointerstitial injury and the progression of chronic kidney disease. Pediatr. Nephrol. 27, 901–909 (2012).

    PubMed  Google Scholar 

  40. Nangaku, M. Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern. Med. 43, 9–17 (2004).

    CAS  PubMed  Google Scholar 

  41. Zeisberg, M. & Neilson, E. G. Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest. 119, 1429–1437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  43. Witek, R. P. et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50, 1421–1430 (2009).

    CAS  PubMed  Google Scholar 

  44. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bussolati, B. et al. Isolation of renal progenitor cells from adult human kidney. Am. J. Pathol. 166, 545–555 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Maeshima, A., Yamashita, S. & Nojima, Y. Identification of renal progenitor-like tubular cells that participate in the regeneration processes of the kidney. J. Am. Soc. Nephrol. 14, 3138–3146 (2003).

    PubMed  Google Scholar 

  47. Smeets, B. et al. Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration. J. Pathol. 229, 645–659 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kang, D. H. et al. Role of the microvascular endothelium in progressive renal disease. J. Am. Soc. Nephrol. 13, 806–816 (2002).

    PubMed  Google Scholar 

  49. Matsumoto, M. et al. Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J. Am. Soc. Nephrol. 15, 1574–1581 (2004).

    PubMed  Google Scholar 

  50. Zoccali, C. Endothelial dysfunction in CKD: a new player in town? Nephrol. Dial. Transplant. 23, 783–785 (2008).

    PubMed  Google Scholar 

  51. Maric-Bilkan, C., Flynn, E. R. & Chade, A. R. Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat. Am. J. Physiol. Renal Physiol. 302, F308–F315 (2012).

    CAS  PubMed  Google Scholar 

  52. Chade, A. R. et al. Beneficial effects of antioxidant vitamins on the stenotic kidney. Hypertension 42, 605–612 (2003).

    CAS  PubMed  Google Scholar 

  53. Pillebout, E. et al. Proliferation and remodeling of the peritubular microcirculation after nephron reduction: association with the progression of renal lesions. Am. J. Pathol. 159, 547–560 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ohashi, R. et al. Peritubular capillary regression during the progression of experimental obstructive nephropathy. J. Am. Soc. Nephrol. 13, 1795–1805 (2002).

    PubMed  Google Scholar 

  55. Clements, M. E., Chaber, C. J., Ledbetter, S. R. & Zuk, A. Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. PLoS ONE 8, e70464 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Renkonen, R., Turunen, J. P., Rapola, J. & Häyry, P. Characterization of high endothelial-like properties of peritubular capillary endothelium during acute renal allograft rejection. Am. J. Pathol. 137, 643–651 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chade, A. R. & Kelsen, S. Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach. Am. J. Physiol. Renal Physiol. 302, F1342–F1350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sun, D. et al. Thrombospondin-1 short hairpin RNA suppresses tubulointerstitial fibrosis in the kidney of ureteral obstruction by ameliorating peritubular capillary injury. Kidney Blood Press. Res. 35, 35–47 (2012).

    PubMed  Google Scholar 

  59. Yamamoto, Y. et al. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 53, 1831–1840 (2004).

    CAS  PubMed  Google Scholar 

  60. Ichinose, K. et al. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 54, 2891–2903 (2005).

    CAS  PubMed  Google Scholar 

  61. Chade, A. R. Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R783–R790 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Pergola, P. E. et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b–4 CKD. Am. J. Nephrol. 33, 469–476 (2011).

    CAS  PubMed  Google Scholar 

  63. Lagaaij, E. L. et al. Endothelial cell chimerism after renal transplantation and vascular rejection. Lancet 357, 33–37 (2001).

    CAS  PubMed  Google Scholar 

  64. Grimm, P. C. et al. Neointimal and tubulointerstitial infiltration by recipient mesenchymal cells in chronic renal-allograft rejection. N. Engl. J. Med. 345, 93–97 (2001).

    CAS  PubMed  Google Scholar 

  65. Fadini, G. P., Losordo, D. & Dimmeler, S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ. Res. 110, 624–637 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).

    CAS  PubMed  Google Scholar 

  67. Anders, H. J. et al. Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRL-Fas(lpr) mice. J. Am. Soc. Nephrol. 15, 1504–1513 (2004).

    CAS  PubMed  Google Scholar 

  68. Ricardo, S. D., van Goor, H. & Eddy, A. A. Macrophage diversity in renal injury and repair. J. Clin. Invest. 118, 3522–3530 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. François, A. et al. B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res. Ther. 15, R168 (2013).

    PubMed  PubMed Central  Google Scholar 

  70. Huaux, F. et al. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J. Immunol. 171, 5470–5481 (2003).

    CAS  PubMed  Google Scholar 

  71. Lebleu, V. S., Sugimoto, H., Miller, C. A., Gattone, V. H. 2nd & Kalluri, R. Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease, Lab. Invest. 88, 284–292 (2008).

    CAS  PubMed  Google Scholar 

  72. Kaviratne, M. et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-β independent. J. Immunol. 173, 4020–4029 (2004).

    CAS  PubMed  Google Scholar 

  73. Elger, M. et al. Nephrogenesis is induced by partial nephrectomy in the elasmobranch Leucoraja erinacea. J. Am. Soc. Nephrol. 14, 1506–1518 (2003).

    PubMed  Google Scholar 

  74. Little, M. H. Regrow or repair: potential regenerative therapies for the kidney. J. Am. Soc. Nephrol. 17, 2390–2401 (2006).

    PubMed  Google Scholar 

  75. Lindoso, R. S., Verdoorn, K. S. & Einicker-Lamas, M. Renal recovery after injury: the role of Pax-2. Nephrol. Dial. Transplant. 24, 2628–2633 (2009).

    CAS  PubMed  Google Scholar 

  76. Narlis, M., Grote, D., Gaitan, Y., Boualia, S. K. & Bouchard, M. Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney, J. Am. Soc. Nephrol. 18, 1121–1129 (2007).

    CAS  PubMed  Google Scholar 

  77. Park, J. S., Valerius, M. T. & McMahon, A. P. Wnt/β-catenin signaling regulates nephron induction during mouse kidney development. Development 134, 2533–2539 (2007).

    CAS  PubMed  Google Scholar 

  78. Bramlage, C. P. et al. Bone morphogenetic protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis. BMC Nephrol. 11, 31 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. Dudley, A. T., Lyons, K. M. & Robertson, E. J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 9, 2795–2807 (1995).

    CAS  PubMed  Google Scholar 

  80. Vukicevic, S. et al. Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J. Clin. Invest. 102, 202–214 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sugimoto, H., Grahovac, G., Zeisberg, M. & Kalluri, R. Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes 56, 1825–1833 (2007).

    CAS  PubMed  Google Scholar 

  82. Morrissey, J. et al. Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J. Am. Soc. Nephrol. 13 (Suppl. 1), S14–S21 (2002).

    CAS  PubMed  Google Scholar 

  83. Zeisberg, M., Shah, A. A. & Kalluri, R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J. Biol. Chem. 280, 8094–8100 (2005).

    CAS  PubMed  Google Scholar 

  84. Swencki-Underwood, B. et al. Expression and characterization of a human BMP-7 variant with improved biochemical properties. Protein Expr. Purif. 57, 312–319 (2008).

    CAS  PubMed  Google Scholar 

  85. Sugimoto, H. et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat. Med. 18, 396–404 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Bachmann, S., Kriz, W., Kuhn, C. & Franke, W. W. Differentiation of cell types in the mammalian kidney by immunofluorescence microscopy using antibodies to intermediate filament proteins and desmoplakins. Histochemistry 77, 365–394 (1983).

    CAS  PubMed  Google Scholar 

  87. Ebrahimi, B. et al. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis. PLoS ONE 8, e67474 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ebrahimi, B. et al. Addition of endothelial progenitor cells to renal revascularization restores medullary tubular oxygen consumption in swine renal artery stenosis. Am. J. Physiol. Renal Physiol. 302, F1478–F1485 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Reinders, M. E. et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl. Med. 2, 107–111 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tan, J. et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307, 1169–1177 (2012).

    CAS  PubMed  Google Scholar 

  91. Didié, M. et al. Parthenogenetic stem cells for tissue-engineered heart repair. J. Clin. Invest. 123, 1285–1298 (2013).

    PubMed  PubMed Central  Google Scholar 

  92. Bhutani, N., Burns, D. M. & Blau, H. M. DNA demethylation dynamics. Cell 146, 866–872 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Van Beneden, K. et al. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis. Toxicol. Appl. Pharmacol. 271, 276–284 (2013).

    CAS  PubMed  Google Scholar 

  94. Manson, S. R., Song, J. B., Hruska, K. A. & Austin, P. F. HDAC dependent transcriptional repression of Bmp-7 potentiates TGF-β mediated renal fibrosis in obstructive uropathy. J. Urol. 191, 242–252 (2013).

    PubMed  PubMed Central  Google Scholar 

  95. Reddy, M. A. et al. Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int. http://dx.doi.org/10.1038/ki.2013.387 (2013).

  96. Tampe, B. et al. Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J. Am. Soc. Nephrol. (in press).

  97. Kolfschoten, I. G. et al. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 121, 849–858 (2005).

    CAS  PubMed  Google Scholar 

  98. Suzuki, T. & Miyata, N. Non-hydroxamate histone deacetylase inhibitors. Curr. Med. Chem. 12, 2867–2880 (2005).

    CAS  PubMed  Google Scholar 

  99. Israili, Z. H. et al. The disposition and pharmacokinetics in humans of 5-azacytidine administered intravenously as a bolus or by continuous infusion. Cancer Res. 36, 1453–1461 (1976).

    CAS  PubMed  Google Scholar 

  100. Chen, J. et al. The metabolic syndrome and chronic kidney disease in US adults. Ann. Intern. Med. 140, 167–174 (2004).

    PubMed  Google Scholar 

  101. Molnar, M. Z. et al. ACE inhibitor and angiotensin receptor blocker use and mortality in patients with chronic kidney disease. J. Am. Coll. Cardiol. http://dx.doi.org/10.1016/j.jacc.2013.10.050 (2013).

  102. Kilbride, H. S. et al. Accuracy of the MDRD (modification of diet in renal disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly. Am. J. Kidney Dis. 61, 57–66 (2013).

    PubMed  Google Scholar 

  103. Stengel, B. et al. The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study. Nephrol. Dial. Transplant. http://dx.doi.org/10.1093/ndt/gft388 (2013).

  104. Gabbai, F. B. et al. Relationship between ambulatory BP and clinical outcomes in patients with hypertensive CKD. Clin. J. Am. Soc. Nephrol. 7, 1770–1776 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. Kanasaki, M., Nagai, T., Kitada, M., Koya, D. & Kanasaki, K. Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors. Fibrogenesis Tissue Repair 4, 25 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Collins, A. J. et al. US Renal Data System Annual Data Report. Am. J. Kidney Dis. 59 (Suppl. 1), evii (2011).

    Google Scholar 

  107. Zeisberg, M. & Müller, G. A. Mechanistic insights into the antifibrotic activity of aliskiren in the kidney, Hypertens. Res. 35, 266–268 (2012).

    CAS  PubMed  Google Scholar 

  108. Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Feldman, D. L. et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 52, 130–136 (2008).

    CAS  PubMed  Google Scholar 

  110. Messerli, F. H. & Bangalore, S. ALTITUDE trial and dual RAS blockade: the alluring but soft science of the surrogate end point. Am. J. Med. 126, e1–e3 (2013).

    PubMed  Google Scholar 

  111. Lecaire, T. J., Klein, B. E., Howard, K. P., Lee, K. E. & Klein, R. Risk for end-stage renal disease over 25 years in the population-based WESDR cohort. Diabetes Care 37, 381–388 (2013).

    PubMed  Google Scholar 

  112. Border, W. A., Okuda, S., Languino, L. R., Sporn, M. B. & Ruoslahti, E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 346, 371–374 (1990).

    CAS  PubMed  Google Scholar 

  113. Border, W. A. et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360, 361–364 (1992).

    CAS  PubMed  Google Scholar 

  114. Isaka, Y. et al. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat. Med. 2, 418–423 (1996).

    CAS  PubMed  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov[online], (2010).

  116. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  117. Garber, K. Companies waver in efforts to target transforming growth factor β in cancer. J. Natl Cancer Inst. 101, 1664–1667 (2009).

    PubMed  Google Scholar 

  118. Akhurst, R. J. TGF-β antagonists: why suppress a tumor suppressor? J. Clin. Invest. 109, 1533–1536 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Massagué, J. How cells read TGF-β signals. Nat. Rev. Mol. Cell Biol. 1, 169–178 (2000).

    PubMed  Google Scholar 

  120. Zeisberg, M. et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 282, 23337–23347 (2007).

    CAS  PubMed  Google Scholar 

  121. Hruska, K. A. et al. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal Physiol. 279, F130–F143 (2000).

    CAS  PubMed  Google Scholar 

  122. Wang, S. & Hirschberg, R. BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells. Am. J. Physiol. Renal Physiol. 284, F1006–F1013 (2003).

    CAS  PubMed  Google Scholar 

  123. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    CAS  PubMed  Google Scholar 

  124. Flier, S. N. et al. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J. Biol. Chem. 285, 20202–20212 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bradham, D. M., Igarashi, A., Potter, R. L. & Grotendorst, G. R. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J. Cell Biol. 114, 1285–1294 (1991).

    CAS  PubMed  Google Scholar 

  126. Nguyen, T. Q. et al. Plasma connective tissue growth factor is an independent predictor of end-stage renal disease and mortality in type 1 diabetic nephropathy. Diabetes Care 31, 1177–1182 (2008).

    PubMed  Google Scholar 

  127. Yokoi, H. et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 15, 1430–1440 (2004).

    CAS  PubMed  Google Scholar 

  128. Guha, M., Xu, Z. G., Tung, D., Lanting, L. & Natarajan, R. Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J. 21, 3355–3368 (2007).

    CAS  PubMed  Google Scholar 

  129. Adler, S. G. et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin. J. Am. Soc. Nephrol. 5, 1420–1428 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Taniguchi, H. et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur. Respir. J. 35, 821–829 (2010).

    CAS  PubMed  Google Scholar 

  131. Shimizu, T. et al. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int. 54, 99–109 (1998).

    CAS  PubMed  Google Scholar 

  132. Ziyadeh, F. N. et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice. Proc. Natl Acad. Sci. USA 97, 8015–8020 (2000).

    CAS  PubMed  Google Scholar 

  133. RamachandraRao, S. P. et al. Pirfenidone is renoprotective in diabetic kidney disease, J. Am. Soc. Nephrol. 20, 1765–1775 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Cho, M. E., Smith, D. C., Branton, M. H., Penzak, S. R. & Kopp, J. B. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 2, 906–913 (2007).

    CAS  PubMed  Google Scholar 

  135. Sharma, K. et al. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 22, 1144–1151 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    CAS  PubMed  Google Scholar 

  137. Sarvaiya, P. J., Guo, D., Ulasov, I., Gabikian, P. & Lesniak, M. S. Chemokines in tumor progression and metastasis. Oncotarget 4, 2171–2185 (2013).

    PubMed  PubMed Central  Google Scholar 

  138. Anders, H. J., Vielhauer, V. & Schlondorff, D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int. 63, 401–415 (2003).

    CAS  PubMed  Google Scholar 

  139. Reich, B. et al. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 84, 78–89 (2013).

    CAS  PubMed  Google Scholar 

  140. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  141. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  142. Sullivan, T. et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am. J. Physiol. Renal Physiol. 305, F1288–F1297 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Hanefeld, M. et al. Orally-administered chemokine receptor CCR2 antagonist CCX140-B in type 2 diabetes: a pilot double-blind, randomized clinical trial. J. Diabetes Metab. 3, 225 (2012).

    Google Scholar 

  144. Inoue, A. et al. The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression. J. Biol. Chem. 264, 14954–14959 (1989).

    CAS  PubMed  Google Scholar 

  145. Arinami, T. et al. Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3. Am. J. Hum. Genet. 48, 990–996 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Karet, F. E. Endothelin peptides and receptors in human kidney, Clin. Sci. (Lond.) 91, 267–273 (1996).

    CAS  Google Scholar 

  147. Dhaun, N., Goddard, J. & Webb, D. J. The endothelin system and its antagonism in chronic kidney disease J. Am. Soc. Nephrol. 17, 943–955 (2006).

    CAS  PubMed  Google Scholar 

  148. Attinà, T., Camidge, R., Newby, D. E. & Webb, D. J. Endothelin antagonism in pulmonary hypertension, heart failure, and beyond. Heart 91, 825–831 (2005).

    PubMed  PubMed Central  Google Scholar 

  149. Wesson, D. E., Simoni, J. & Green, D. F. Reduced extracellular pH increases endothelin-1 secretion by human renal microvascular endothelial cells. J. Clin. Invest. 101, 578–583 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Hocher, B. & Paul, M. Transgenic animal models for the analysis of the renal endothelin system. Nephrol. Dial. Transplant. 15, 935–937 (2000).

    CAS  PubMed  Google Scholar 

  151. Saito, Y. et al. Application of monoclonal antibodies for endothelin to hypertensive research. Hypertension 15, 734–738 (1990).

    CAS  PubMed  Google Scholar 

  152. Kuc, R. & Davenport, A. P. Comparison of endothelin-A and endothelin-B receptor distribution visualized by radioligand binding versus immunocytochemical localization using subtype selective antisera. J. Cardiovasc. Pharmacol. 44 (Suppl. 1), S224–S226 (2004).

    CAS  PubMed  Google Scholar 

  153. Benigni, A. et al. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int. 44, 440–444 (1993).

    CAS  PubMed  Google Scholar 

  154. Opocenský, M. et al. Late-onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension 48, 965–971 (2006).

    PubMed  Google Scholar 

  155. Boffa, J. J., Tharaux, P. L., Dussaule, J. C. & Chatziantoniou, C. Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension 37, 490–496 (2001).

    CAS  PubMed  Google Scholar 

  156. Gómez-Garre, D. et al. Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. Hypertension 27, 885–892 (1996).

    PubMed  Google Scholar 

  157. Fukuda, K. et al. Role of endothelin as a mitogen in experimental glomerulonephritis in rats, Kidney Int. 49, 1320–1329 (1996).

    CAS  PubMed  Google Scholar 

  158. Benigni, A. et al. Renoprotective effect of contemporary blocking of angiotensin II and endothelin-1 in rats with membranous nephropathy. Kidney Int. 54, 353–359 (1998).

    CAS  PubMed  Google Scholar 

  159. Saleh, M. A., Pollock, J. S. & Pollock, D. M. Distinct actions of endothelin A-selective versus combined endothelin A/B receptor antagonists in early diabetic kidney disease. J. Pharmacol. Exp. Ther. 338, 263–270 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Wenzel, R. R. et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J. Am. Soc. Nephrol. 20, 655–664 (2009).

    PubMed  PubMed Central  Google Scholar 

  161. Mann, J. F. et al. Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 21, 527–535 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Chen, Y. M., Wu, K. D., Tsai, T. J. & Hsieh, B. S. Pentoxifylline inhibits PDGF-induced proliferation of and TGF-β-stimulated collagen synthesis by vascular smooth muscle cells. J. Mol. Cell Cardiol. 31, 773–783 (1999).

    CAS  PubMed  Google Scholar 

  163. Strutz, F. et al. Effects of pentoxifylline, pentifylline and gamma-interferon on proliferation, differentiation, and matrix synthesis of human renal fibroblasts. Nephrol. Dial. Transplant. 15, 1535–1546 (2000).

    CAS  PubMed  Google Scholar 

  164. Lin, S. L. et al. Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J. Am. Soc. Nephrol. 13, 2916–2929 (2002).

    CAS  PubMed  Google Scholar 

  165. Rodriguez-Morán, M. et al. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: a double-blind, placebo-controlled randomized trial. Clin. Nephrol. 66, 3–10 (2006).

    PubMed  Google Scholar 

  166. Perkins, R. M. et al. Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am. J. Kidney Dis. 53, 606–616 (2009).

    CAS  PubMed  Google Scholar 

  167. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  168. Zalba, G. et al. Is the balance between nitric oxide and superoxide altered in spontaneously hypertensive rats with endothelial dysfunction? Nephrol. Dial. Transplant. 16 (Suppl. 1), 2–5 (2001).

    CAS  PubMed  Google Scholar 

  169. Firoozi, F., Longhurst, P. A. & White, M. D. In vivo and in vitro response of corpus cavernosum to phosphodiesterase-5 inhibition in the hypercholesterolaemic rabbit. BJU Int. 96, 164–168 (2005).

    CAS  PubMed  Google Scholar 

  170. Dousa, T. P. Cyclic-3′,5′-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int. 55, 29–62 (1999).

    CAS  PubMed  Google Scholar 

  171. Lau, D. H., Mikhailidis, D. P. & Thompson, C. S. The effect of vardenafil (a PDE type 5 inhibitor) on renal function in the diabetic rabbit: a pilot study. In Vivo 21, 851–854 (2007).

    CAS  PubMed  Google Scholar 

  172. Jeong, K. H. et al. Effects of sildenafil on oxidative and inflammatory injuries of the kidney in streptozotocin-induced diabetic rats. Am. J. Nephrol. 29, 274–282 (2009).

    CAS  PubMed  Google Scholar 

  173. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  174. Wilcox, C. S. Reactive oxygen species: roles in blood pressure and kidney function. Curr. Hypertens. Rep. 4, 160–166 (2002).

    PubMed  Google Scholar 

  175. Touyz, R. M. Reactive oxygen species in vascular biology: role in arterial hypertension. Expert Rev. Cardiovasc. Ther. 1, 91–106 (2003).

    CAS  PubMed  Google Scholar 

  176. Vaziri, N. D. & Rodriguez-Iturbe, B. Mechanisms of disease: oxidative stress and inflammation in the pathogenesis of hypertension. Nat. Clin. Pract. Nephrol. 2, 582–593 (2006).

    CAS  PubMed  Google Scholar 

  177. Mueller, C. F., Laude, K., McNally, J. S. & Harrison, D. G. ATVB in focus: redox mechanisms in blood vessels, Arterioscler. Thromb. Vasc. Biol. 25, 274–278 (2005).

    CAS  PubMed  Google Scholar 

  178. Griendling, K. K. NADPH oxidases: new regulators of old functions. Antioxid. Redox Signal. 8, 1443–1445 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Lassegue, B. & Clempus, R. E. Vascular NAD(P)H oxidases: specific features, expression, and regulation, Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R277–R297 (2003).

    CAS  PubMed  Google Scholar 

  180. Rajagopalan, S. et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J. Clin. Invest. 97, 1916–1923 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Virdis, A., Neves, M. F., Amiri, F., Touyz, R. M. & Schiffrin, E. L. Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J. Hypertens. 22, 535–542 (2004).

    CAS  PubMed  Google Scholar 

  182. Aoyama, T. et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56, 2316–2327 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Fortuño, A. et al. Association of increased phagocytic NADPH oxidase-dependent superoxide production with diminished nitric oxide generation in essential hypertension. J. Hypertens. 22, 2169–2175 (2004).

    PubMed  Google Scholar 

  184. Higashi, Y. et al. Endothelial function and oxidative stress in renovascular hypertension. N. Engl. J. Med. 346, 1954–1962 (2002).

    CAS  PubMed  Google Scholar 

  185. Lip, G. Y. et al. Oxidative stress in malignant and non-malignant phase hypertension. J. Hum. Hypertens. 16, 333–336 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.Z. is supported by German Research Foundation (DFG) grants ZE523/2-1 and ZE523/3-1.

Author information

Authors and Affiliations

  1. Department of Nephrology and Rheumatology, Göttingen University Medical Center, Georg August University, Robert Koch Straße 40, Göttingen, 37075, Germany

    Desiree Tampe & Michael Zeisberg

Authors
  1. Desiree Tampe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Zeisberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript and edited it prior to submission.

Corresponding author

Correspondence to Michael Zeisberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tampe, D., Zeisberg, M. Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol 10, 226–237 (2014). https://doi.org/10.1038/nrneph.2014.14

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2014.14

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing