Journal of Molecular Medicine

, Volume 91, Issue 5, pp 549–559 | Cite as

Molecular targets for treatment of kidney fibrosis



Renal fibrosis is the culmination of processes driven by signaling pathways involving transforming growth factor-β family of cytokines, connective-tissue growth factor, nuclear factor κB, Wnt/β-catenin, Notch, and other growth factors. Many studies in experimental animal models have directly targeted these pathways and demonstrated efficacy in mitigating renal fibrosis. However, only a small fraction of these approaches have been attempted in human and even fewer have been successfully translated to clinical use for patient with kidney diseases. Drugs with proven efficacy for treatment of kidney diseases and tissue fibrosis exert some of their effects by interfering with components of these pathways. This review considers key molecular mediators of renal fibrosis and their potential as targets for treatment of renal fibrosis.


Kidney Fibrosis HIPK2 Signaling pathways Treatment 


  1. 1.
    Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57:365–380PubMedCrossRefGoogle Scholar
  2. 2.
    Striker GE, Schainuck LI, Cutler RE, Benditt EP (1970) Structural-functional correlations in renal disease. I. A method for assaying and classifying histopathologic changes in renal disease. Hum Pathol 1:615–630PubMedCrossRefGoogle Scholar
  3. 3.
    Nath KA (1992) Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis: Off J Nat Kidney Found 20:1–17Google Scholar
  4. 4.
    Mackensen-Haen S, Bader R, Grund KE, Bohle A (1981) Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate. Clin Nephrol 15:167–171PubMedGoogle Scholar
  5. 5.
    Boor P, Sebekova K, Ostendorf T, Floege J (2007) Treatment targets in renal fibrosis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 22:3391–3407CrossRefGoogle Scholar
  6. 6.
    Boor P, Ostendorf T, Floege J (2010) Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 6:643–656PubMedCrossRefGoogle Scholar
  7. 7.
    Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol: JASN 21:1819–1834PubMedCrossRefGoogle Scholar
  8. 8.
    Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696PubMedCrossRefGoogle Scholar
  9. 9.
    Sanchez-Lopez E, Rayego S, Rodrigues-Diez R, Rodriguez JS, Rodrigues-Diez R, Rodriguez-Vita J, Carvajal G, Aroeira LS, Selgas R, Mezzano SA et al (2009) CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kappaB. J Am Soc Nephrol: JASN 20:1513–1526PubMedCrossRefGoogle Scholar
  10. 10.
    Esteban V, Lorenzo O, Ruperez M, Suzuki Y, Mezzano S, Blanco J, Kretzler M, Sugaya T, Egido J, Ruiz-Ortega M (2004) Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol: JASN 15:1514–1529PubMedCrossRefGoogle Scholar
  11. 11.
    Leroy V, De Seigneux S, Agassiz V, Hasler U, Rafestin-Oblin ME, Vinciguerra M, Martin PY, Feraille E (2009) Aldosterone activates NF-kappaB in the collecting duct. J Am Soc Nephrol: JASN 20:131–144PubMedCrossRefGoogle Scholar
  12. 12.
    Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol: JASN 17:2974–2984PubMedCrossRefGoogle Scholar
  13. 13.
    Zoja C, Garcia PB, Remuzzi G (2009) The role of chemokines in progressive renal disease. Front Biosci: J Virtual Libr 14:1815–1822CrossRefGoogle Scholar
  14. 14.
    Jones LK, O’Sullivan KM, Semple T, Kuligowski MP, Fukami K, Ma FY, Nikolic-Paterson DJ, Holdsworth SR, Kitching AR (2009) IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol, Dial, Transplant: Off Publ Eur Dial Transplant Assoc - Eur Renal Assoc 24:3024–3032CrossRefGoogle Scholar
  15. 15.
    Semedo P, Correa-Costa M, Antonio Cenedeze M, Maria Avancini Costa Malheiros D, Antonia dos Reis M, Shimizu MH, Seguro AC, Pacheco-Silva A, Saraiva Camara NO (2009) Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells 27:3063–3073Google Scholar
  16. 16.
    Shimizu H, Maruyama S, Yuzawa Y, Kato T, Miki Y, Suzuki S, Sato W, Morita Y, Maruyama H, Egashira K et al (2003) Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J Am Soc Nephrol: JASN 14:1496–1505PubMedCrossRefGoogle Scholar
  17. 17.
    Gong R, Rifai A, Tolbert EM, Biswas P, Centracchio JN, Dworkin LD (2004) Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and RANTES. J Am Soc Nephrol: JASN 15:2868–2881PubMedCrossRefGoogle Scholar
  18. 18.
    Anders HJ, Schlondorff D (2007) Toll-like receptors: emerging concepts in kidney disease. Curr Opin Nephrol Hypertens 16:177–183PubMedCrossRefGoogle Scholar
  19. 19.
    Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, Sheerin NS, Wong W (2010) Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction. Kidney Int 78:351–362PubMedCrossRefGoogle Scholar
  20. 20.
    Kelly CJ, Zurier RB, Krakauer KA, Blanchard N, Neilson EG (1987) Prostaglandin E1 inhibits effector T cell induction and tissue damage in experimental murine interstitial nephritis. J Clin Investig 79:782–789PubMedCrossRefGoogle Scholar
  21. 21.
    Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK (2008) Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol, Dial, Transplant: Off Publ Eur Dial Transplant Assoc - Eur Renal Assoc 23:842–852CrossRefGoogle Scholar
  22. 22.
    Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L, Chang DH, Mahajan D, Coombs J, Wang YM, Alexander SI et al (2007) Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72:290–299PubMedCrossRefGoogle Scholar
  23. 23.
    Wada T, Sakai N, Matsushima K, Kaneko S (2007) Fibrocytes: a new insight into kidney fibrosis. Kidney Int 72:269–273PubMedCrossRefGoogle Scholar
  24. 24.
    Gandolfo MT, Jang HR, Bagnasco SM, Ko GJ, Agreda P, Satpute SR, Crow MT, King LS, Rabb H (2009) Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76:717–729PubMedCrossRefGoogle Scholar
  25. 25.
    Miyazawa S, Hotta O, Doi N, Natori Y, Nishikawa K, Natori Y (2004) Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats. Kidney Int 65:2228–2237PubMedCrossRefGoogle Scholar
  26. 26.
    Grande MT, Lopez-Novoa JM (2009) Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 5:319–328PubMedCrossRefGoogle Scholar
  27. 27.
    Picard N, Baum O, Vogetseder A, Kaissling B, Le Hir M (2008) Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat. Histochem Cell Biol 130:141–155PubMedCrossRefGoogle Scholar
  28. 28.
    Iwano M, Fischer A, Okada H, Plieth D, Xue C, Danoff TM, Neilson EG (2001) Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol Ther: J Am Soc Gene Ther 3:149–159CrossRefGoogle Scholar
  29. 29.
    Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627PubMedCrossRefGoogle Scholar
  30. 30.
    Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol: JASN 19:2282–2287PubMedCrossRefGoogle Scholar
  31. 31.
    Zeisberg M, Kalluri R (2008) Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front Bioscie: J Virtual Libr 13:6991–6998CrossRefGoogle Scholar
  32. 32.
    Zeisberg M, Duffield JS (2010) Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol: JASN 21:1247–1253PubMedCrossRefGoogle Scholar
  33. 33.
    Kriz W, Kaissling B, Le Hir M (2011) Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J Clin Investig 121:468–474PubMedCrossRefGoogle Scholar
  34. 34.
    Schlondorff DO (2008) Overview of factors contributing to the pathophysiology of progressive renal disease. Kidney Int 74:860–866PubMedCrossRefGoogle Scholar
  35. 35.
    Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791PubMedCrossRefGoogle Scholar
  36. 36.
    Bottinger EP (2007) TGF-beta in renal injury and disease. Semin Nephrol 27:309–320PubMedCrossRefGoogle Scholar
  37. 37.
    Lan HY (2011) Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 7:1056–1067PubMedCrossRefGoogle Scholar
  38. 38.
    Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286–1292PubMedCrossRefGoogle Scholar
  39. 39.
    Bitzer M, Sterzel RB, Bottinger EP (1998) Transforming growth factor-beta in renal disease. Kidney Blood Press Res 21:1–12PubMedCrossRefGoogle Scholar
  40. 40.
    Bottinger EP, Kopp JB (1998) Lessons from TGF-beta transgenic mice. Miner Electrolyte Metab 24:154–160PubMedCrossRefGoogle Scholar
  41. 41.
    Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E (1990) Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346:371–374PubMedCrossRefGoogle Scholar
  42. 42.
    Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E (1992) Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360:361–364PubMedCrossRefGoogle Scholar
  43. 43.
    Sharma K, Jin Y, Guo J, Ziyadeh FN (1996) Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45:522–530PubMedCrossRefGoogle Scholar
  44. 44.
    Isaka Y, Akagi Y, Ando Y, Tsujie M, Sudo T, Ohno N, Border WA, Noble NA, Kaneda Y, Hori M et al (1999) Gene therapy by transforming growth factor-beta receptor-IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int 55:465–475PubMedCrossRefGoogle Scholar
  45. 45.
    Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K (2000) Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 97:8015–8020PubMedCrossRefGoogle Scholar
  46. 46.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341–347PubMedCrossRefGoogle Scholar
  47. 47.
    Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL (2000) Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Molecular cell 6:1365–1375PubMedCrossRefGoogle Scholar
  48. 48.
    Li JH, Huang XR, Zhu HJ, Oldfield M, Cooper M, Truong LD, Johnson RJ, Lan HY (2004) Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 18:176–178CrossRefGoogle Scholar
  49. 49.
    Chung AC, Zhang H, Kong YZ, Tan JJ, Huang XR, Kopp JB, Lan HY (2010) Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling. J Am Soc Nephrol: JASN 21:249–260PubMedCrossRefGoogle Scholar
  50. 50.
    Wang W, Huang XR, Canlas E, Oka K, Truong LD, Deng C, Bhowmick NA, Ju W, Bottinger EP, Lan HY (2006) Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res 98:1032–1039PubMedCrossRefGoogle Scholar
  51. 51.
    Yang F, Chung AC, Huang XR, Lan HY (2009) Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. Hypertension 54:877–884PubMedCrossRefGoogle Scholar
  52. 52.
    Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ, Natarajan R (2007) MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A 104:3432–3437PubMedCrossRefGoogle Scholar
  53. 53.
    Wang B, Herman-Edelstein M, Koh P, Burns W, Jandeleit-Dahm K, Watson A, Saleem M, Goodall GJ, Twigg SM, Cooper ME et al (2010) E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta. Diabetes 59:1794–1802PubMedCrossRefGoogle Scholar
  54. 54.
    Chung AC, Huang XR, Meng X, Lan HY (2010) miR-192 mediates TGF-beta/Smad3-driven renal fibrosis. J Am Soc Nephrol: JASN 21:1317–1325PubMedCrossRefGoogle Scholar
  55. 55.
    Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D (2010) Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol: JASN 21:438–447PubMedCrossRefGoogle Scholar
  56. 56.
    Liu Y, Taylor NE, Lu L, Usa K, Cowley AW Jr, Ferreri NR, Yeo NC, Liang M (2010) Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes. Hypertension 55:974–982PubMedCrossRefGoogle Scholar
  57. 57.
    Kato M, Wang L, Putta S, Wang M, Yuan H, Sun G, Lanting L, Todorov I, Rossi JJ, Natarajan R (2010) Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-{beta}-induced collagen expression in kidney cells. J Biol Chem 285:34004–34015PubMedCrossRefGoogle Scholar
  58. 58.
    Zhang Z, Peng H, Chen J, Chen X, Han F, Xu X, He X, Yan N (2009) MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice. FEBS Lett 583:2009–2014PubMedCrossRefGoogle Scholar
  59. 59.
    Wang Q, Wang Y, Minto AW, Wang J, Shi Q, Li X, Quigg RJ (2008) MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 22:4126–4135CrossRefGoogle Scholar
  60. 60.
    Kasinath BS, Feliers D (2011) The complex world of kidney microRNAs. Kidney Int 80:334–337PubMedCrossRefGoogle Scholar
  61. 61.
    Kantharidis P, Wang B, Carew RM, Lan HY (2011) Diabetes complications: the microRNA perspective. Diabetes 60:1832–1837PubMedCrossRefGoogle Scholar
  62. 62.
    Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161PubMedCrossRefGoogle Scholar
  63. 63.
    Yaswen L, Kulkarni AB, Fredrickson T, Mittleman B, Schiffman R, Payne S, Longenecker G, Mozes E, Karlsson S (1996) Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse. Blood 87:1439–1445PubMedGoogle Scholar
  64. 64.
    Wan YY, Flavell RA (2008) TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol 28:647–659PubMedCrossRefGoogle Scholar
  65. 65.
    Soma J, Sugawara T, Huang YD, Nakajima J, Kawamura M (2002) Tranilast slows the progression of advanced diabetic nephropathy. Nephron 92:693–698PubMedCrossRefGoogle Scholar
  66. 66.
    Soma J, Sato K, Saito H, Tsuchiya Y (2006) Effect of tranilast in early-stage diabetic nephropathy. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 21:2795–2799CrossRefGoogle Scholar
  67. 67.
    Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB (2007) Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol: CJASN 2:906–913PubMedCrossRefGoogle Scholar
  68. 68.
    Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan TA et al (2011) Pirfenidone for diabetic nephropathy. J Am Soc Nephrol: JASN 22:1144–1151PubMedCrossRefGoogle Scholar
  69. 69.
    Kelly DJ, Zhang Y, Gow R, Gilbert RE (2004) Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J Am Soc Nephrol: JASN 15:2619–2629PubMedCrossRefGoogle Scholar
  70. 70.
    Holmes DR Jr, Savage M, LaBlanche JM, Grip L, Serruys PW, Fitzgerald P, Fischman D, Goldberg S, Brinker JA, Zeiher AM et al (2002) Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 106:1243–1250PubMedCrossRefGoogle Scholar
  71. 71.
    Li BX, Tang YT, Wang W, Xie YY, Wang NS, Yuan QJ, Zhang FF, Peng ZZ, Hu GY, Tao LJ (2011) Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. Mol Cell Biochem 354:263–273PubMedCrossRefGoogle Scholar
  72. 72.
    Takakuta K, Fujimori A, Chikanishi T, Tanokura A, Iwatsuki Y, Yamamoto M, Nakajima H, Okada M, Itoh H (2010) Renoprotective properties of pirfenidone in subtotally nephrectomized rats. Eur J Pharmacol 629:118–124PubMedCrossRefGoogle Scholar
  73. 73.
    RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, Okada S, Shaw MA, Sharma K (2009) Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol: JASN 20:1765–1775PubMedCrossRefGoogle Scholar
  74. 74.
    Vilayur E, Harris DC (2009) Emerging therapies for chronic kidney disease: what is their role? Nat Rev Nephrol 5:375–383PubMedCrossRefGoogle Scholar
  75. 75.
    No authors listed (1997) Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 349: 1857–1863.Google Scholar
  76. 76.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462PubMedCrossRefGoogle Scholar
  77. 77.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860PubMedCrossRefGoogle Scholar
  78. 78.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869PubMedCrossRefGoogle Scholar
  79. 79.
    Ruster C, Wolf G (2011) Angiotensin II as a morphogenic cytokine stimulating renal fibrogenesis. J Am Soc Nephrol: JASN 22:1189–1199PubMedCrossRefGoogle Scholar
  80. 80.
    Liu Z, Huang XR, Lan HY (2012) Smad3 mediates ANG II-induced hypertensive kidney disease in mice. American journal of physiology Renal physiology 302:F986–F997PubMedCrossRefGoogle Scholar
  81. 81.
    Wolf G, Mueller E, Stahl RA, Ziyadeh FN (1993) Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta. J Clin Investig 92:1366–1372PubMedCrossRefGoogle Scholar
  82. 82.
    Wolf G, Ziyadeh FN, Stahl RA (1999) Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells. J Mol Med (Berl) 77:556–564CrossRefGoogle Scholar
  83. 83.
    Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine & growth factor reviews 8:171–179CrossRefGoogle Scholar
  84. 84.
    Liu BC, Sun J, Chen Q, Ma KL, Ruan XZ, Phillips AO (2003) Role of connective tissue growth factor in mediating hypertrophy of human proximal tubular cells induced by angiotensin II. Am J Nephrol 23:429–437PubMedCrossRefGoogle Scholar
  85. 85.
    Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14:627–644PubMedGoogle Scholar
  86. 86.
    Phillips MI, Kagiyama S (2002) Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs 3:569–577PubMedGoogle Scholar
  87. 87.
    Mezzano SA, Ruiz-Ortega M, Egido J (2001) Angiotensin II and renal fibrosis. Hypertension 38:635–638PubMedCrossRefGoogle Scholar
  88. 88.
    Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature medicine 9:964–968PubMedCrossRefGoogle Scholar
  89. 89.
    Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W Jr, Bey P, Rusckowski M et al (2012) Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nature medicine 18:396–404PubMedCrossRefGoogle Scholar
  90. 90.
    Abreu JG, Ketpura NI, Reversade B, De Robertis EM (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nature cell biology 4:599–604PubMedGoogle Scholar
  91. 91.
    Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 18:816–827CrossRefGoogle Scholar
  92. 92.
    Chen XM, Qi W, Pollock CA (2009) CTGF and chronic kidney fibrosis. Front Biosci (Schol Ed) 1:132–141Google Scholar
  93. 93.
    Ito Y, Aten J, Bende RJ, Oemar BS, Rabelink TJ, Weening JJ, Goldschmeding R (1998) Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 53:853–861PubMedCrossRefGoogle Scholar
  94. 94.
    Yokoi H, Sugawara A, Mukoyama M, Mori K, Makino H, Suganami T, Nagae T, Yahata K, Fujinaga Y, Tanaka I et al (2001) Role of connective tissue growth factor in profibrotic action of transforming growth factor-beta: a potential target for preventing renal fibrosis. American journal of kidney diseases: the official journal of the National Kidney Foundation 38:S134–S138CrossRefGoogle Scholar
  95. 95.
    Guha M, Xu ZG, Tung D, Lanting L, Natarajan R (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 21:3355–3368CrossRefGoogle Scholar
  96. 96.
    Yokoi H, Mukoyama M, Nagae T, Mori K, Suganami T, Sawai K, Yoshioka T, Koshikawa M, Nishida T, Takigawa M et al (2004) Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol: JASN 15:1430–1440PubMedCrossRefGoogle Scholar
  97. 97.
    Wang Q, Usinger W, Nichols B, Gray J, Xu L, Seeley TW, Brenner M, Guo G, Zhang W, Oliver N et al (2011) Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. Fibrogenesis Tissue Repai 4:4CrossRefGoogle Scholar
  98. 98.
    Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C, Bolton WK, Lee T, Li D, Neff TB, Urquilla PR, Sewell KL (2010) Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol: CJASN 5:1420–1428PubMedCrossRefGoogle Scholar
  99. 99.
    Tsai TJ, Lin RH, Chang CC, Chen YM, Chen CF, Ko FN, Teng CM (1995) Vasodilator agents modulate rat glomerular mesangial cell growth and collagen synthesis. Nephron 70:91–99PubMedCrossRefGoogle Scholar
  100. 100.
    Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005) Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol: JASN 16:2702–2713PubMedCrossRefGoogle Scholar
  101. 101.
    Lin SL, Chen YM, Chien CT, Chiang WC, Tsai CC, Tsai TJ (2002) Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol: JASN 13:2916–2929PubMedCrossRefGoogle Scholar
  102. 102.
    Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ (2008) Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kidney Dis: the official journal of the National Kidney Foundation 52:464–474CrossRefGoogle Scholar
  103. 103.
    Navarro JF, Mora C, Rivero A, Gallego E, Chahin J, Macia M, Mendez ML, Garcia J (1999) Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. American journal of kidney diseases: the official journal of the National Kidney Foundation 33:458–463CrossRefGoogle Scholar
  104. 104.
    Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM (2009) Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. American journal of kidney diseases: the official journal of the National Kidney Foundation 53:606–616CrossRefGoogle Scholar
  105. 105.
    Shan D, Wu HM, Yuan QY, Li J, Zhou RL, Liu GJ (2012) Pentoxifylline for diabetic kidney disease. Cochrane Database Syst Rev 2:CD006800PubMedGoogle Scholar
  106. 106.
    Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832PubMedCrossRefGoogle Scholar
  107. 107.
    Nathan C, Ding A (2010) Nonresolving inflammation. Cell 140:871–882PubMedCrossRefGoogle Scholar
  108. 108.
    Sanz AB, Sanchez-Nino MD, Ramos AM, Moreno JA, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A (2010) NF-kappaB in renal inflammation. J Am Soc Nephrol: JASN 21:1254–1262PubMedCrossRefGoogle Scholar
  109. 109.
    Doi TS, Takahashi T, Taguchi O, Azuma T, Obata Y (1997) NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. The Journal of experimental medicine 185:953–961PubMedCrossRefGoogle Scholar
  110. 110.
    Liu Y (2010) New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol: JASN 21:212–222PubMedCrossRefGoogle Scholar
  111. 111.
    Pulkkinen K, Murugan S, Vainio S (2008) Wnt signaling in kidney development and disease. Organogenesis 4:55–59PubMedCrossRefGoogle Scholar
  112. 112.
    He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. Journal of the American Society of Nephrology: JASN 20:765–776PubMedCrossRefGoogle Scholar
  113. 113.
    Hao S, He W, Li Y, Ding H, Hou Y, Nie J, Hou FF, Kahn M, Liu Y (2011) Targeted inhibition of beta-catenin/CBP signaling ameliorates renal interstitial fibrosis. Journal of the American Society of Nephrology: JASN 22:1642–1653PubMedCrossRefGoogle Scholar
  114. 114.
    Hwang I, Seo EY, Ha H (2009) Wnt/beta-catenin signaling: a novel target for therapeutic intervention of fibrotic kidney disease. Archives of pharmacal research 32:1653–1662PubMedCrossRefGoogle Scholar
  115. 115.
    Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T, Si H, Thomas DB, Pullman JM, Melamed ML et al (2010) Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int 78:514–522PubMedCrossRefGoogle Scholar
  116. 116.
    Bielesz B, Sirin Y, Si H, Niranjan T, Gruenwald A, Ahn S, Kato H, Pullman J, Gessler M, Haase VH et al (2010) Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Investig 120:4040–4054PubMedCrossRefGoogle Scholar
  117. 117.
    Sirin Y, Susztak K (2012) Notch in the kidney: development and disease. J Pathol 226:394–403PubMedCrossRefGoogle Scholar
  118. 118.
    Rossini M, Cheunsuchon B, Donnert E, Ma LJ, Thomas JW, Neilson EG, Fogo AB (2005) Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney Int 68:2621–2628PubMedCrossRefGoogle Scholar
  119. 119.
    Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG (2002) Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int 61:1714–1728PubMedCrossRefGoogle Scholar
  120. 120.
    Strutz F, Zeisberg M, Hemmerlein B, Sattler B, Hummel K, Becker V, Muller GA (2000) Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int 57:1521–1538PubMedCrossRefGoogle Scholar
  121. 121.
    Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine & growth factor reviews 15:255–273CrossRefGoogle Scholar
  122. 122.
    Ostendorf T, Rong S, Boor P, Wiedemann S, Kunter U, Haubold U, van Roeyen CR, Eitner F, Kawachi H, Starling G et al (2006) Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol: JASN 17:1054–1062PubMedCrossRefGoogle Scholar
  123. 123.
    Boor P, Konieczny A, Villa L, Kunter U, van Roeyen CR, LaRochelle WJ, Smithson G, Arrol S, Ostendorf T, Floege J (2007) PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 22:1323–1331CrossRefGoogle Scholar
  124. 124.
    Eitner F, Bucher E, van Roeyen C, Kunter U, Rong S, Seikrit C, Villa L, Boor P, Fredriksson L, Backstrom G et al (2008) PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. Journal of the American Society of Nephrology: JASN 19:281–289PubMedCrossRefGoogle Scholar
  125. 125.
    Melenhorst WB, Mulder GM, Xi Q, Hoenderop JG, Kimura K, Eguchi S, van Goor H (2008) Epidermal growth factor receptor signaling in the kidney: key roles in physiology and disease. Hypertension 52:987–993PubMedCrossRefGoogle Scholar
  126. 126.
    Lautrette A, Li S, Alili R, Sunnarborg SW, Burtin M, Lee DC, Friedlander G, Terzi F (2005) Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nature medicine 11:867–874PubMedCrossRefGoogle Scholar
  127. 127.
    Chen J, Chen JK, Nagai K, Plieth D, Tan M, Lee TC, Threadgill DW, Neilson EG, Harris RC (2012) EGFR signaling promotes TGFbeta-dependent renal fibrosis. J Am Soc Nephrol: JASN 23:215–224PubMedCrossRefGoogle Scholar
  128. 128.
    Liu N, Guo JK, Pang M, Tolbert E, Ponnusamy M, Gong R, Bayliss G, Dworkin LD, Yan H, Zhuang S (2012) Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol: JASN 23:854–867PubMedCrossRefGoogle Scholar
  129. 129.
    Liu Y (2004) Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action. American journal of physiology Renal physiology 287:F7–F16PubMedCrossRefGoogle Scholar
  130. 130.
    Takayama H, LaRochelle WJ, Sabnis SG, Otsuka T, Merlino G (1997) Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor. Laboratory investigation; a journal of technical methods and pathology 77:131–138PubMedGoogle Scholar
  131. 131.
    Wang SN, LaPage J, Hirschberg R (2000) Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int 57:1002–1014PubMedCrossRefGoogle Scholar
  132. 132.
    Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T (2005) Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Critical reviews in oncology/hematology 53:35–69PubMedCrossRefGoogle Scholar
  133. 133.
    Jin Y, Ratnam K, Chuang PY, Fan Y, Zhong Y, Dai Y, Mazloom AR, Chen EY, D’Agati V, Xiong H et al (2012) A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nature medicine 18:580–588PubMedCrossRefGoogle Scholar
  134. 134.
    Calzado MA, Renner F, Roscic A, Schmitz ML (2007) HIPK2: a versatile switchboard regulating the transcription machinery and cell death. Cell Cycle 6:139–143PubMedCrossRefGoogle Scholar
  135. 135.
    Ots M, Mackenzie HS, Troy JL, Rennke HG, Brenner BM (1998) Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol: JASN 9:224–230PubMedGoogle Scholar
  136. 136.
    Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K, Ritz E (2003) Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol: JASN 14:2833–2842PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Peter Y. Chuang
    • 1
  • Madhav C. Menon
    • 1
  • John C. He
    • 1
    • 2
  1. 1.Division of NephrologyMount Sinai School of MedicineNew YorkUSA
  2. 2.NephrologyJames J. Peters Veterans Affairs Medical CenterNew YorkUSA

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