Hills, Claire E. and Squires, Paul E.. (2011) The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine & Growth Factor Reviews . ISSN 1359-6101

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Abstract

Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signalling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signalling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH):	Transforming growth factors-beta, Kidneys -- Fibrosis, Diabetic nephropathies, Epithelial cells, Myofibroblasts
Journal or Publication Title:	Cytokine & Growth Factor Reviews
Publisher:	Elsevier Ltd
ISSN:	1359-6101
Date:	2011
Identification Number:	10.1016/j.cytogfr.2011.06.002
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Diabetes UK, Diabetes Research & Wellness Foundation (DRWF), European Foundation for the Study of Diabetes (EFSD), Janssen Pharmaceutical Ltd., University of Warwick, Wellcome Trust (London, England)
Grant number:	11/0004215 (DUK)
References:	[1] US Renal Data System. USRDS (2003) Annual data report: atlas of end-stage renal disease in the United States. Bethesda. MD. National Institute of Health. National Institute of Diabetes and Digestive and Kidney Disease. [2] Wolfe RA, Port FK, Webb RL, Bloembergen WE, Hirth R, Young EW, Ojo AO, Strawderman RL, Parekh R, Stack A, Tedeschi PJ, Hulbert-Shearon T, Ashby VB, Callard S, Hanson J, Jain A, Meyers-Purkiss A, Roys E, Brown P, Wheeler JR, Jones CA, Greer JW, Agodoa LY. Introduction to the excerpts from the United States Renal Data System 1999 Annual Data Report. Am J Kidney Dis. 1999; 34:S1-3. [3] Soldatos G, Cooper ME. DN. Important pathophysiologic mechanisms. Diabetes Res Clin Pract. 2008; 82:S75-9. [4] Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC. Structural functional relationships in DN. J Clin Invest 1984; 74:1143-55. [5] Steffes MW, Osterby R, Chavers B, Mauer SM. Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 1989; 38:1077-81. [6] Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol 2003;14:1358–73. [7] Nangaku M. Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern. Med 2004; 43:9–17. [8] Wolf G. New insights into the pathophysiology of diabetic nephropathy: from hemodynamics to molecular pathology. Eur J Clin Invest 2004; 34:785–96 . [9] Hills CE, Squires PE. TGF-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol 2010; 31:68-74. [10] Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110:341–350. [11] Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, Shafritz DA, Bottinger EP. Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 2006; 26: 654–67. [12] Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15:740–746. [13] Rastaldi MP, Ferrario F, Giardino L, Dell'Antonio G, Grillo C, Grillo P, Strutz F, Müller GA, Colasanti G, D'Amico G. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 2002; 62:137–146. [14] Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med 2004; 82:175–181. [15] Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, Chugh S, Danesh FR. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med 2008; 233: 4–11. [16] Sharma K, Ziyadeh F. Hyperglycaemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 1996; 44:1139–1146. [17] Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1194; 10:1286-92. [18] Bieke F. Schrijvers, An S. De Vriese and Allan Flyvbjerg. From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines. Endocrine Reviews 2004; 25:971-1010. [19] Dan DC, Hoffman BB, Hong SW. Therapy with antisense TGF-1 oligodeoxynucleotides reduces kidney weight and matrix mRNAs in diabetic mice. Am J Physiol Renal Physiol 2000; 278:F628–F634. [20] Ziyadeh FN. The extracellular matrix in DN. Am J Kidney Dis 1992; 22: 36-744. [21] Chen S, Hong SW, Iglesias-de la Cruz MC, Isono M, Casaretto A, Ziyadeh FN. The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. Ren Fail 2001; 23:471–481. [22] Sharma K, Jin Y, Guo J, Ziyadeh FN. 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 1996; 45:522-30. [23] Border WA, Yamamoto T, Noble NA. Transforming growth factor beta in diabetic nephropathy. Diabetes Metab Rev 1996; 12:309-39. [24] Ziyadeh FN, Sharma K, Ericksen M, Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta. J Clin Invest 1994; 93:536-42. [25] Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev. 2008; 4:39-45. [26] Bae JS, Kim IS, Rezaie AR. Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1. J Cell Physiol 2010; 225:233-9. [27] Reiniger N, Lau K, McCalla D, Eby B, Cheng B, Lu Y, Qu W, Quadri N, Ananthakrishnan R, Furmansky M, Rosario R, Song F, Rai V, Weinberg A, Friedman R, Ramasamy R, D'Agati V, Schmidt AM. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes. 2010; 59:2043-54. [28] Slattery C, Ryan MP, McMorrow T. Protein kinase C beta overexpression induces fibrotic effects in human proximal tubular epithelial cells. Int J Biochem Cell Biol. 2008; 40:2218-29. [29] Iwano M, Kubo A, Nishino T, Sato H, Nishioka H, Akai Y, Kurioka H, Fujii Y, Kanauchi M, Shiiki H, Dohi K. Quantification of glomerular TGF-beta 1 mRNA in patients with diabetes mellitus. Kidney Int. 1996; 49:1120-6. [30] Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kurnik BR, Kurnik PB, Weisberg LS. Increased renal production of transforming growth factor-beta1 in patients with type II diabetes. Diabetes. 1997; 46:854-9. [31] Wrighton KH, Lin X, Feng XH. Phospho-control of TGF-beta superfamily signaling. Cell Res 2009; 19:8-20. [32] Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 2007; 8:970-82. [33] Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol 2002; 13:2600–2610. [34] Pelton RW, Saxena B, Jones M, Moses HL, Gold LI. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991; 115:1091-105. [35] Massagué J, Chen YG. Controlling TGF-beta signaling. Genes Dev 2000; 14: 627–644. [36] Kristine C. Nyhan , Noel Faherty , Gregg Murray, Laurence Berubé Cooey , Catherine Godson , John K. Crean, Derek P. Brazil. Jagged/Notch signalling is required for a subset of TGFβ1 responses in human kidneyepithelial cells. Biochimica et Biophysica Acta 2010; 1803:1386–1395. [37] Gentry LE, Lioubin MN, Purchio AF, Marquardt H. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol 1988; 8:4162-8. [38] Ribeiro SM, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem. 1999; 274:13586-93. [39] Dennler S, Itoh S, Vivien D, Dijke P, Huet S, Gauthier J. Direct binding of smad3 and smad4 to critical TGF- inducible elements in the promoter of the human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17:3091-3100. [40] Itoh S, Thorikay M, Kowanetz M, Moustakas A, Itoh F, Heldin CH, ten Dijke P. Elucidation of Smad requirement in transforming growth factor-beta type I receptor-induced responses. J Biol Chem 2003; 278:3751–3761. [41] Kim SJ, Angel P, Lafyatis R, Hattori K, Kim KY, Sporn MB, Karin M, Roberts AB. Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol. 1990; 12:1492–1497. [42] Van Obberghen-Schilling E, Roche NS, Flanders KC, Sporn MB, Roberts AB. Transforming growth factor β1 positively regulates its own expression in normal and transformed cells. J Biol Chem 1988; 263:7741–7746. [43] Zhang M, Fraser D, Phillips A. ERK, p38, and Smad signaling pathways differentially regulate transforming growth factor-beta1 autoinduction in proximal tubular epithelial cells. Am J Pathol 2006; 169:1282-93. [44] Flanders KC, Holder MG, Winokur TS. Autoinduction of mRNA and protein expression for transforming growth factor-beta S in cultured cardiac cells. J Mol Cell Cardiol 1995; 27:805–812. [45] Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 2003; 112:1486–1494. [46] Piek E, Ju WJ, Heyer J, Escalante-Alcalde D, Stewart CL, Weinstein M, Deng C, Kucherlapati R, Böttinger EP, Roberts AB. Functional characterisation of transforming growth factor β signaling in Smad2- and Smad3 deficient fibroblasts. J Biol Chem 2001; 276:19945–19953. [47] Wang W, Koka V, Lan HY. Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology 2005; 10:48-56. [48] Yang J, Zhang X, Li Y, Liu Y. Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling. J Am Soc Nephrol 2003; 14:3167-77. [49] Yeh YC, Wei WC, Wang YK, Lin SC, Sung JM, Tang MJ. Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis. Am J Pathol 2010; 177:1743-54. [50] Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, Shafritz DA and Bottinger EP. Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 2006; 26:654-67. [51] Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 2007; 101:9-33. [52] Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic programming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005; 16:1987–2002. [53] Luo K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev 2004; 14:65–70. [54] Yang F, Huang XR, Chung AC, Hou CC, Lai KN, Lan HY. Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol 2010; 221:390-401. [55] Tan R, Zhang J, Tan X, Zhang X, Yang J, Liu Y. Downregulation of SnoN expression in obstructive nephropathy is mediated by an enhanced ubiquitin-dependent degradation. J Am Soc Nephrol 2006; 17:2781-91. [56] Lan HY. Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci 2008; 13:4984-92. [57] Li JH, Zhu HJ, Huang XR, Lai KN, Johnson RJ, Lan HY. Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol 2002; 13:1464-72. [58] Nakao A, Okumura K, Ogawa H. Smad7: a new key player in TGF-beta-associated disease. Trends Mol Med 2002; 8:361-3. [59] Park SH. Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 2005; 38:9-16 [60] Yan X, Liu Z, Chen Y. Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai) 2009; 41:263-72. [61] Luo K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev 2004; 14:65–70. [62] Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Suzuki S, Kitagawa M, Hishida A. Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney Int 2006; 69:1733–1740. [63] Tan R, He W, Lin X, Kiss LP, Liu Y. Smad ubiquitination regulatory factor-2 in the fibrotic kidney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol 2008; 294:F1076-83. [64] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119:1420-8. [65] Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol 1982; 95:333-9. [66] Zheng G, Lyons JG, Tan TK, Wang Y, Hsu TT, Min D, Succar L, Rangan GK, Hu M, Henderson BR, Alexander SI, Harris DC. Disruption of E-cadherin by matrix metalloproteinase directly mediates epithelial-mesenchymal transition downstream of transforming growth factor-beta1 in renal tubular epithelial cells. Am J Pathol 2009; 175:580-91. [67] Masszi A, Fan L, Rosivall L, McCulloch CA, Rotstein OD, Mucsi I, Kapus A. Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta [68] Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest. 2009; 119:1417-9. [69] Nawshad A, Lagamba D, Polad A, Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 2005; 179:11–23. [70] Zavadil J, Böttinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005; 24:5764-74. [71] Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006; 172:973–981. [72] Okada H, Ban S, Nagao S, Takahashi H, Suzuki H, Neilson EG. Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation. Kidney Int 2000; 58:587–597. [73] Galichon P, Hertig A. Epithelial to mesenchymal transition as a biomarker in renal fibrosis: are we ready for the bedside? Fibrogenesis Tissue Repair. 2011; 6:4:11. [74] Badid C, Desmouliere A, Babici D, Hadj-Aissa A, McGregor B, Lefrancois N, Touraine JL, Laville M. Interstitial expression of alpha-SMA: an early marker of chronic renal allograft dysfunction. Nephrol Dial Transplant 2002; 17:1993-1998. [75] Vongwiwatana A, Tasanarong A, Rayner DC, Melk A, Halloran PF. Epithelial to mesenchymal transition during late deterioration of human kidney transplants: The role of tubular cells in fibrogenesis. Am J Transplant 2005; 5:1367–1374. [76] Kida Y, Duffield JS. Frontiers in Research: Chronic Kidney Diseases: The pivotal role of pericytes in kidney fibrosis. Clin Exp Pharmacol Physiol. 2011; doi: 10.1111/j.1440-1681.2011.05531. [77] Schrimpf C, Duffield JS. Mechanisms of fibrosis: the role of the pericyte. Curr Opin Nephrol Hypertens. 2011; 20:297-305. [78] Quaggin SE, Kapus A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 2011; Mar 23. [advance online publication], 23 March 2011; doi:10.1038/ki.2011.77. [79] Strutz F, Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol. 2006; 17: 2992-8. [80] Lin SL, Kisseleva T, Brenner DA, Duffield JS. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 2008;173:1617-27. [81] Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 2010; 176:85-97. [82] Keeley EC, Mehrad B, Strieter RM. Fibrocytes: bringing new insights into mechanisms of inflammation and fibrosis. Int J Biochem Cell Biol. 2010; 42:535-42. [83] Zeisberg M, Duffield JS. Resolved: EMT produces fibroblasts in the kidney.J Am Soc Nephrol 2010; 21:1247-53. [84] Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 2006;103:13180-5. [85] Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007; 282:23337-47. [86] Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, Kalluri R.J. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. Biol Chem. 2010;285:20202-12. [87] Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG. Identification and characterization of a fibroblast
URI:	http://wrap.warwick.ac.uk/id/eprint/36436

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