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Mechanisms of Interstitial Fibrosis in Diabetic Nephropathy

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Diabetic Nephropathy

Abstract

In studies regarding the progression of diabetic nephropathy (DN), tubular injury, such as tubular atrophy and tubulointerstitial fibrosis, has been long underestimated, and research has been focused mainly on glomerular pathology. Recently, more studies evaluated tubular damage, since it became obvious that tubulointerstitial fibrosis and tubular atrophy show a major correlation with the declined renal function in DN. Hyperglycemia induces tubular atrophy in DN through mechanisms that are identical to those thought to cause interstitial fibrogenesis. The biologic processes leading to kidney fibrosis are not simply just rigid mechanisms but rather a complex interaction between pathologic changes in renal cells and the pathobiologic activity of profibrotic factors. Multiple cell types and numerous pathways are activated in the kidney during the course of diabetes, and all individually or collectively play a role in the development and progression of interstitial fibrosis. A comprehensive understanding of the underlying mechanisms and downstream pathways involved in the tubulointerstitial fibrosis is mandatory to develop groundbreaking therapeutic options and novel clinical strategies in the treatment of DN.

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References

  1. Ina K, Kitamura H, Tatsukawa S, Takayama T, Fujikura Y, Shimada T. Transformation of interstitial fibroblasts and tubulointerstitial fibrosis in diabetic nephropathy. Med Electron Microsc. 2002;35:87–95.

    Article  PubMed  Google Scholar 

  2. Kolset SO, Reinholt FP, Jenssen T. Diabetic nephropathy and extracellular matrix. J Histochem Cytochem. 2012;60:976–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Iwano M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. Curr Opin Nephrol Hypertens. 2004;13:279–84.

    Article  PubMed  Google Scholar 

  4. Li R, Chung AC, Dong Y, Yang W, Zhong X, Lan HY. The microrna mir-433 promotes renal fibrosis by amplifying the tgf-beta/smad3-azin1 pathway. Kidney Int. 2013;84:1129–44.

    Article  CAS  PubMed  Google Scholar 

  5. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol. 2000;15:290–301.

    Article  CAS  PubMed  Google Scholar 

  6. Lindquist JA, Mertens PR. Myofibroblasts, regeneration or renal fibrosis–is there a decisive hint? Nephrol Dial Transplant. 2013;28:2678–81.

    Article  CAS  PubMed  Google Scholar 

  7. Phillips AO, Steadman R. Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. Histol Histopathol. 2002;17:247–52.

    CAS  PubMed  Google Scholar 

  8. Qi W, Twigg S, Chen X, Polhill TS, Poronnik P, Gilbert RE, Pollock CA. Integrated actions of transforming growth factor-beta1 and connective tissue growth factor in renal fibrosis. Am J Physiol Renal Physiol. 2005;288:F800–9.

    Article  CAS  PubMed  Google Scholar 

  9. Qi W, Chen X, Poronnik P, Pollock CA. The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol. 2006;38:1–5.

    Article  CAS  PubMed  Google Scholar 

  10. Loeffler I, Wolf G. Epithelial-to-mesenchymal transition in diabetic nephropathy: fact or fiction? Cell. 2015;4:631–52.

    Article  Google Scholar 

  11. Kriz W, Kaissling B, Le Hir M. Epithelial-mesenchymal transition (emt) in kidney fibrosis: fact or fantasy? J Clin Invest. 2011;121:468–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zeisberg M, Duffield JS. Resolved: Emt produces fibroblasts in the kidney. J Am Soc Nephrol JASN. 2010;21:1247–53.

    Article  PubMed  Google Scholar 

  13. Liu Y. New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol JASN. 2010;21:212–22.

    Article  CAS  PubMed  Google Scholar 

  14. Grgic I, Duffield JS, Humphreys BD. The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr Nephrol. 2012;27:183–93.

    Article  PubMed  Google Scholar 

  15. Quaggin SE, Kapus A. Scar wars: mapping the fate of epithelial-mesenchymal-myofibroblast transition. Kidney Int. 2011;80:41–50.

    Article  PubMed  Google Scholar 

  16. Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int. 2007;71:846–54.

    Article  CAS  PubMed  Google Scholar 

  17. Strutz F, Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol JASN. 2006;17:2992–8.

    Article  CAS  PubMed  Google Scholar 

  18. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011;7:684–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Boor P, Floege J. The renal (myo-)fibroblast: a heterogeneous group of cells. Nephrol Dial Transplant. 2012;27:3027–36.

    Article  PubMed  Google Scholar 

  20. Lovisa S, Zeisberg M, Kalluri R. Partial epithelial-to-mesenchymal transition and other new mechanisms of kidney fibrosis. Trends Endocrinol Metab. 2016;27:681–95.

    Article  CAS  PubMed  Google Scholar 

  21. Farris AB, Colvin RB. Renal interstitial fibrosis: mechanisms and evaluation in: current opinion in nephrology and hypertension. Curr Opin Nephrol Hypertens. 2012;21:289–300.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Meran S, Steadman R. Fibroblasts and myofibroblasts in renal fibrosis. Int J Exp Pathol. 2011;92:158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Johnson DW, Saunders HJ, Baxter RC, Field MJ, Pollock CA. Paracrine stimulation of human renal fibroblasts by proximal tubule cells. Kidney Int. 1998;54:747–57.

    Article  CAS  PubMed  Google Scholar 

  24. Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne). 2013;4:7.

    Google Scholar 

  25. Wolf G. Cell cycle regulation in diabetic nephropathy. Kidney Int Suppl. 2000;77:S59–66.

    Article  CAS  PubMed  Google Scholar 

  26. Reich B, Schmidbauer K, Gomez MR, Hermann FJ, Gobel N, Bruhl H, Ketelsen I, Talke Y, Mack M. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int. 2013;84:78–89.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19:1047–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mack M, Yanagita M. Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. 2015;87:297–307.

    Article  PubMed  Google Scholar 

  30. Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J Physiol Regul Integr Comp Physiol. 2011;300:R1009–22.

    Article  CAS  PubMed  Google Scholar 

  31. Bonventre JV. Can we target tubular damage to prevent renal function decline in diabetes? Semin Nephrol. 2012;32:452–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wolf G, Ziyadeh FN. Molecular mechanisms of diabetic renal hypertrophy. Kidney Int. 1999;56:393–405.

    Article  CAS  PubMed  Google Scholar 

  33. Thomasova D, Anders HJ. Cell cycle control in the kidney. Nephrol Dial Transplant. 2015;30:1622–30.

    Article  CAS  PubMed  Google Scholar 

  34. Verzola D, Gandolfo MT, Gaetani G, Ferraris A, Mangerini R, Ferrario F, Villaggio B, Gianiorio F, Tosetti F, Weiss U, et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2008;295:F1563–73.

    Article  CAS  PubMed  Google Scholar 

  35. Satriano J, Mansoury H, Deng A, Sharma K, Vallon V, Blantz RC, Thomson SC. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol. 2010;299:C374–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in g2/m mediates kidney fibrosis after injury. Nat Med. 2010;16:535–43. 531p following 143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Loeffler I, Wolf G. Transforming growth factor-beta and the progression of renal disease. Nephrol Dial Transplant. 2014;29(Suppl 1):i37–45.

    Article  CAS  PubMed  Google Scholar 

  38. Hills CE, Squires PE. The role of tgf-beta and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev. 2011;22:131–9.

    CAS  PubMed  Google Scholar 

  39. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol JASN. 2010;21:1819–34.

    Article  CAS  PubMed  Google Scholar 

  40. Simon N, Hertig A. Alteration of fatty acid oxidation in tubular epithelial cells: from acute kidney injury to renal fibrogenesis. Front Med (Lausanne). 2015;2:52.

    Google Scholar 

  41. Kang HM, Ahn SH, Choi P, Ko YA, Han SH, Chinga F, Park AS, Tao J, Sharma K, Pullman J, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21:37–46.

    Article  CAS  PubMed  Google Scholar 

  42. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55:561–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang S, Mitu GM, Hirschberg R. Osmotic polyuria: an overlooked mechanism in diabetic nephropathy. Nephrol Dial Transplant. 2008;23:2167–72.

    Article  CAS  PubMed  Google Scholar 

  44. Gorriz JL, Martinez-Castelao A. Proteinuria: detection and role in native renal disease progression. Transplant Rev. 2012;26:3–13.

    Article  Google Scholar 

  45. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24:96–103.

    Article  CAS  PubMed  Google Scholar 

  46. Tojo A, Kinugasa S. Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol. 2012;2012:481520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Birn H, Christensen EI. Renal albumin absorption in physiology and pathology. Kidney Int. 2006;69:440–9.

    Article  CAS  PubMed  Google Scholar 

  48. Wolf G, Schroeder R, Ziyadeh FN, Stahl RA. Albumin up-regulates the type ii transforming growth factor-beta receptor in cultured proximal tubular cells. Kidney Int. 2004;66:1849–58.

    Article  CAS  PubMed  Google Scholar 

  49. Bottinger EP, Bitzer M. Tgf-beta signaling in renal disease. J Am Soc Nephrol JASN. 2002;13:2600–10.

    Article  PubMed  Google Scholar 

  50. Balakumar P, Chakkarwar VA, Krishan P, Singh M. Vascular endothelial dysfunction: A tug of war in diabetic nephropathy? Biomed Pharmacother = Biomed Pharmacother. 2009;63:171–9.

    Article  CAS  PubMed  Google Scholar 

  51. Guerrot D, Dussaule JC, Kavvadas P, Boffa JJ, Chadjichristos CE, Chatziantoniou C. Progression of renal fibrosis: the underestimated role of endothelial alterations. Fibrogenesis Tissue Repair. 2012;5:S15.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Dussaule JC, Guerrot D, Huby AC, Chadjichristos C, Shweke N, Boffa JJ, Chatziantoniou C. The role of cell plasticity in progression and reversal of renal fibrosis. Int J Exp Pathol. 2011;92:151–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol JASN. 2008;19:2282–7.

    Article  PubMed  Google Scholar 

  54. Schrimpf C, Duffield JS. Mechanisms of fibrosis: the role of the pericyte. Curr Opin Nephrol Hypertens. 2011;20:297–305.

    Article  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ruger BM, Hasan Q, Greenhill NS, Davis PF, Dunbar PR, Neale TJ. Mast cells and type viii collagen in human diabetic nephropathy. Diabetologia. 1996;39:1215–22.

    Article  CAS  PubMed  Google Scholar 

  57. Dronavalli S, Duka I, Bakris GL. The pathogenesis of diabetic nephropathy. Nat Clin Pract Endocrinol Metab. 2008;4:444–52.

    Article  CAS  PubMed  Google Scholar 

  58. He T, Xiong J, Nie L, Yu Y, Guan X, Xu X, Xiao T, Yang K, Liu L, Zhang D, et al. Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating ampk/nox4/ros pathway. J Mol Med (Berlin, Germany). 2016;94:1359–71.

    Article  CAS  Google Scholar 

  59. Lau X, Zhang Y, Kelly DJ, Stapleton DI. Attenuation of armanni-ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, ft011. Diabetologia. 2013;56:675–9.

    Article  CAS  PubMed  Google Scholar 

  60. Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol JASN. 2003;14:S254–8.

    Article  CAS  PubMed  Google Scholar 

  61. Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. The importance of diabetic nephropathy in current nephrological practice. Nephrol Dial Transplant. 2003;18:1716–25.

    Article  CAS  PubMed  Google Scholar 

  62. Daroux M, Prevost G, Maillard-Lefebvre H, Gaxatte C, D'Agati VD, Schmidt AM, Boulanger E. Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab. 2010;36:1–10.

    Article  CAS  PubMed  Google Scholar 

  63. Gasparitsch M, Arndt AK, Pawlitschek F, Oberle S, Keller U, Kasper M, Bierhaus A, Schaefer F, Weber LT, Lange-Sperandio B. Rage-mediated interstitial fibrosis in neonatal obstructive nephropathy is independent of nf-kappab activation. Kidney Int. 2013;84:911–9.

    Article  CAS  PubMed  Google Scholar 

  64. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Investig. 2004;34:785–96.

    Article  CAS  Google Scholar 

  65. Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993;90:1814–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sharma K, McGowan TA. Tgf-beta in diabetic kidney disease: role of novel signaling pathways. Cytokine Growth Factor Rev. 2000;11:115–23.

    Article  CAS  PubMed  Google Scholar 

  67. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol JASN. 2003;14:1358–73.

    Article  CAS  PubMed  Google Scholar 

  68. Wei X, Xia Y, Li F, Tang Y, Nie J, Liu Y, Zhou Z, Zhang H, Hou FF. Kindlin-2 mediates activation of tgf-beta/smad signaling and renal fibrosis. J Am Soc Nephrol JASN. 2013;24:1387–98.

    Article  CAS  PubMed  Google Scholar 

  69. Hirschberg R. Kindlin-2: a new player in renal fibrogenesis. J Am Soc Nephrol JASN. 2013;24:1339–40.

    Article  CAS  PubMed  Google Scholar 

  70. Lam S, van der Geest RN, Verhagen NA, van Nieuwenhoven FA, Blom IE, Aten J, Goldschmeding R, Daha MR, van Kooten C. Connective tissue growth factor and igf-i are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes. 2003;52:2975–83.

    Article  CAS  PubMed  Google Scholar 

  71. Vasylyeva TL, Ferry RJ Jr. Novel roles of the igf-igfbp axis in etiopathophysiology of diabetic nephropathy. Diabetes Res Clin Pract. 2007;76:177–86.

    Article  CAS  PubMed  Google Scholar 

  72. Simon-Tillaux N, Hertig A. Snail and kidney fibrosis. Nephrol Dial Transplant. 2017;32:224–33.

    PubMed  Google Scholar 

  73. Loeffler I, Liebisch M, Daniel C, Amann K, Wolf G. Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db/db mice. Nephrol Dial Transplant. 2017;32(12):2017–34.

    Article  PubMed  Google Scholar 

  74. Bai X, Geng J, Zhou Z, Tian J, Li X. Microrna-130b improves renal tubulointerstitial fibrosis via repression of snail-induced epithelial-mesenchymal transition in diabetic nephropathy. Sci Rep. 2016;6:20475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A, Arevalo M, Rowe RG, Weiss SJ, Lopez-Novoa JM, Nieto MA. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015;21:989–97.

    Article  CAS  PubMed  Google Scholar 

  76. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kida Y, Asahina K, Teraoka H, Gitelman I, Sato T. Twist relates to tubular epithelial-mesenchymal transition and interstitial fibrogenesis in the obstructed kidney. J Histochem Cytochem. 2007;55:661–73.

    Article  CAS  PubMed  Google Scholar 

  78. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Wu CC, Hagos Y, Burckhardt BC, Pentcheva-Hoang T, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21:998–1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vinod PB. Pathophysiology of diabetic nephropathy. Clin Queries Nephrol. 2012;1:121–6.

    Article  Google Scholar 

  80. Durvasula RV, Shankland SJ. The renin-angiotensin system in glomerular podocytes: mediator of glomerulosclerosis and link to hypertensive nephropathy. Curr Hypertens Rep. 2006;8:132–8.

    Article  CAS  PubMed  Google Scholar 

  81. Arora MK, Singh UK. Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update. Vasc Pharmacol. 2013;58:259–71.

    Article  CAS  Google Scholar 

  82. Wolf G, Ziyadeh FN, Stahl RA. Angiotensin ii stimulates expression of transforming growth factor beta receptor type ii in cultured mouse proximal tubular cells. J Mol Med (Berlin, Germany). 1999;77:556–64.

    Article  CAS  Google Scholar 

  83. Chen J, Chen JK, Nagai K, Plieth D, Tan M, Lee TC, Threadgill DW, Neilson EG, Harris RC. Egfr signaling promotes tgfbeta-dependent renal fibrosis. J Am Soc Nephrol JASN. 2012;23:215–24.

    Article  CAS  PubMed  Google Scholar 

  84. Wolf G, Ziyadeh FN. The role of angiotensin ii in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis (The Official Journal of the National Kidney Foundation). 1997;29:153–63.

    Article  CAS  Google Scholar 

  85. Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (vegf) in renal pathophysiology. Kidney Int. 2004;65:2003–17.

    Article  CAS  PubMed  Google Scholar 

  86. Senthil D, Choudhury GG, McLaurin C, Kasinath BS. Vascular endothelial growth factor induces protein synthesis in renal epithelial cells: a potential role in diabetic nephropathy. Kidney Int. 2003;64:468–79.

    Article  CAS  PubMed  Google Scholar 

  87. Hills CE, Squires PE. Tgf-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol. 2010;31:68–74.

    Article  CAS  PubMed  Google Scholar 

  88. Liu Y. Hepatocyte growth factor and the kidney. Curr Opin Nephrol Hypertens. 2002;11:23–30.

    Article  PubMed  Google Scholar 

  89. Mizuno S, Nakamura T. Suppressions of chronic glomerular injuries and tgf-beta 1 production by hgf in attenuation of murine diabetic nephropathy. Am J Physiol Renal Physiol. 2004;286:F134–43.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang Y, Zhang Q. Bone morphogenetic protein-7 and gremlin: new emerging therapeutic targets for diabetic nephropathy. Biochem Biophys Res Commun. 2009;383:1–3.

    Article  CAS  PubMed  Google Scholar 

  91. Wang SN, Lapage J, Hirschberg R. Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol JASN. 2001;12:2392–9.

    CAS  PubMed  Google Scholar 

  92. Nguyen TQ, Roestenberg P, van Nieuwenhoven FA, Bovenschen N, Li Z, Xu L, Oliver N, Aten J, Joles JA, Vial C, et al. Ctgf inhibits bmp-7 signaling in diabetic nephropathy. J Am Soc Nephrol JASN. 2008;19:2098–107.

    Article  CAS  PubMed  Google Scholar 

  93. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R. Bmp-7 counteracts tgf-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003;9:964–8.

    Article  CAS  PubMed  Google Scholar 

  94. Wang S, Chen Q, Simon TC, Strebeck F, Chaudhary L, Morrissey J, Liapis H, Klahr S, Hruska KA. Bone morphogenic protein-7 (bmp-7), a novel therapy for diabetic nephropathy. Kidney Int. 2003;2037-2049:63.

    Google Scholar 

  95. Yang J, Liu Y. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001;159:1465–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol JASN. 2004;15:1–12.

    Article  CAS  PubMed  Google Scholar 

  97. Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol JASN. 2006;17:2484–94.

    Article  CAS  PubMed  Google Scholar 

  98. Li J, Qu X, Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol. 2009;175:1380–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kizu A, Medici D, Kalluri R. Endothelial-mesenchymal transition as a novel mechanism for generating myofibroblasts during diabetic nephropathy. Am J Pathol. 2009;175:1371–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Loeffler I, Liebisch M, Wolf G. Collagen viii influences epithelial phenotypic changes in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2012;303:F733–45.

    Article  CAS  PubMed  Google Scholar 

  101. Li J, Qu X, Yao J, Caruana G, Ricardo SD, Yamamoto Y, Yamamoto H, Bertram JF. Blockade of endothelial-mesenchymal transition by a smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes. 2010;59:2612–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against tgfbeta-induced epithelial-to-mesenchymal transition (emt): from cancer stem cells to aging-associated fibrosis. Cell Cycle. 2010;9:4461–8.

    Article  CAS  PubMed  Google Scholar 

  103. Takiyama Y, Harumi T, Watanabe J, Fujita Y, Honjo J, Shimizu N, Makino Y, Haneda M. Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of hif-1alpha expression and oxygen metabolism. Diabetes. 2011;60:981–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Singh DK, Winocour P, Farrington K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat Clin Pract Nephrol. 2008;4:216–26.

    Article  CAS  PubMed  Google Scholar 

  105. Loeffler I, Wolf G. The role of hypoxia and morg1 in renal injury. Eur J Clin Investig. 2015;45:294–302.

    Article  CAS  Google Scholar 

  106. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol JASN. 2006;17:17–25.

    Article  CAS  PubMed  Google Scholar 

  107. Caramori ML, Mauer M. Diabetes and nephropathy. Curr Opin Nephrol Hypertens. 2003;12:273–82.

    Article  CAS  PubMed  Google Scholar 

  108. Duran-Salgado MB, Rubio-Guerra AF. Diabetic nephropathy and inflammation. World J Diabetes. 2014;5:393–8.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Navarro-Gonzalez JF, Mora-Fernandez C, de Fuentes MM, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327–40.

    Article  CAS  PubMed  Google Scholar 

  110. Sharma D, Bhattacharya P, Kalia K, Tiwari V. Diabetic nephropathy: new insights into established therapeutic paradigms and novel molecular targets. Diabetes Res Clin Pract. 2017;128:91–108.

    Article  CAS  PubMed  Google Scholar 

  111. Murea M, Freedman BI, Parks JS, Antinozzi PA, Elbein SC, Ma L. Lipotoxicity in diabetic nephropathy: the potential role of fatty acid oxidation. Clin J Am Soc Nephrol. 2010;5:2373–9.

    Article  CAS  PubMed  Google Scholar 

  112. Proctor G, Jiang T, Iwahashi M, Wang Z, Li J, Levi M. Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and ove26 mice with type 1 diabetes. Diabetes. 2006;55:2502–9.

    Article  CAS  PubMed  Google Scholar 

  113. Stadler K, Goldberg IJ, Susztak K. The evolving understanding of the contribution of lipid metabolism to diabetic kidney disease. Curr Diab Rep. 2015;15:40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Simpson K, Wonnacott A, Fraser DJ, Bowen T. Micrornas in diabetic nephropathy: from biomarkers to therapy. Curr Diab Rep. 2016;16:35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Qin W, Chung AC, Huang XR, Meng XM, Hui DS, Yu CM, Sung JJ, Lan HY. Tgf-beta/smad3 signaling promotes renal fibrosis by inhibiting mir-29. J Am Soc Nephrol JASN. 2011;22:1462–74.

    Article  CAS  PubMed  Google Scholar 

  116. Maric C, Sullivan S. Estrogens and the diabetic kidney. Gend Med. 2008;5(Suppl A):S103–13.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Maric C. Sex, diabetes and the kidney. Am J Physiol Renal Physiol. 2009;296:F680–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Harvey JN. The influence of sex and puberty on the progression of diabetic nephropathy and retinopathy. Diabetologia. 2011;54:1943–5.

    Article  CAS  PubMed  Google Scholar 

  119. Vomastek T, Schaeffer HJ, Tarcsafalvi A, Smolkin ME, Bissonette EA, Weber MJ. Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specificagonists. Proc Natl Acad Sci U S A. 2004;101:6981–6.

    Article  CAS  Google Scholar 

  120. Hopfer U, Hopfer H, Jablonski K, Stahl RA, Wolf G. The novel wd-repeat protein morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (phd3). J Biol Chem. 2006;281:8645–55.

    Article  CAS  PubMed  Google Scholar 

  121. Sage H, Trueb B, Bornstein P. Biosynthetic and structural properties of endothelial cell type viii collagen. J Biol Chem. 1983;258:13391–401.

    CAS  PubMed  Google Scholar 

  122. Gerth J, Cohen CD, Hopfer U, Lindenmeyer MT, Sommer M, Grone HJ, Wolf G. Collagen type viii expression in human diabetic nephropathy. Eur J Clin Investig. 2007;37:767–73.

    Article  CAS  Google Scholar 

  123. Hopfer U, Hopfer H, Meyer-Schwesinger C, Loeffler I, Fukai N, Olsen BR, Stahl RA, Wolf G. Lack of type viii collagen in mice ameliorates diabetic nephropathy. Diabetes. 2009;58:1672–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital Jena, Jena, Germany

    Ivonne Loeffler & Gunter Wolf

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  1. Ivonne Loeffler
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  2. Gunter Wolf
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Correspondence to Gunter Wolf .

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  1. Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Joris J. Roelofs

  2. Department of Internal Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Liffert Vogt

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Loeffler, I., Wolf, G. (2019). Mechanisms of Interstitial Fibrosis in Diabetic Nephropathy. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_15

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