Current Diabetes Reports

, Volume 12, Issue 4, pp 414–422 | Cite as

Anti-Fibrosis Therapy and Diabetic Nephropathy

Microvascular Complications—Nephropathy (B Roshan, Section Editor)

Abstract

Diabetes mellitus is rapidly becoming a global health issue that may overtake cancer during the next two decades as it covertly affects multiple organ systems that goes undiagnosed long after the onset. A number of complications are associated with poorly controlled hyperglycemia. Diabetic nephropathy is one of the most common complications of diabetes mellitus. Other than angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blocker (ARB) there is not much in the armamentarium with which to treat patients with overt diabetic nephropathy. Research points towards a multifactorial etiology and complex interplay of several pathogenic pathways that can contribute to the declining kidney function in diabetes. Patients with diabetic nephropathy (and with any chronic kidney disease) eventually develop kidney fibrosis. Despite the financial and labor investment spent on determining the basic mechanism of fibrosis, not much progress has been made in terms of therapeutic targets available to us today. This may be in part due to paucity in the experimental animal models available. However, there now seems to be a concerted effort from several pharmaceutical companies to develop a drug that would halt/delay the process of fibrosis, if not reverse it. This review discusses the current state of research in the field while staying within the context of diabetic nephropathy.

Keywords

Kidney Diabetes Fibrosis Nephropathy Anti-Fibrosis therapy 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Soldatos G, Cooper ME. Diabetic nephropathy: important pathophysiologic mechanisms. Diabetes Res Clin Pract. 2008;82 Suppl 1:S75–9.PubMedCrossRefGoogle Scholar
  3. 3.
    de Boer IH, Rue TC, Cleary PA, Lachin JM, Molitch ME, Steffes MW, et al. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med. 2011;171:412–20.PubMedCrossRefGoogle Scholar
  4. 4.
    • Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS. In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int. 2010;77:57–64. The study argues that CKD can exist in the absence of proteinuria.PubMedCrossRefGoogle Scholar
  5. 5.
    • Dwyer JP, Parving HH, Hunsicker LG, Ravid M, Remuzzi G, Lewis JB. Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND Study. Cardiorenal Med. 2012;2:1–10. Data from the study further supports the idea of CKD in the absence of proteinuria.PubMedCrossRefGoogle Scholar
  6. 6.
    Orchard TJ, Dorman JS, Maser RE, Becker DJ, Drash AL, Ellis D, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990;39:1116–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007;2:906–13.PubMedCrossRefGoogle Scholar
  8. 8.
    RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol. 2009;20:1765–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Racusen LC, Solez K, Colvin R. Fibrosis and atrophy in the renal allograft: interim report and new directions. Am J Transplant. 2002;2:203–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, et al. Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant. 2007;7:518–26.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Bucala R. Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol. 2008;5:36–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, et al. Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension. 2011;57:314–22.PubMedCrossRefGoogle Scholar
  14. 14.
    •• D’Agati V, Schmidt AM. RAGE and the pathogenesis of chronic kidney disease. Nat Rev Nephrol. 2010;6:352–60. Details the importance of RAGE in CKD.PubMedCrossRefGoogle Scholar
  15. 15.
    Sebekova K, Klenovicsova K, Ferenczova J, Hedvig J, Podracka L, Heidland A. Advanced oxidation protein products and advanced glycation end products in children and adolescents with chronic renal insufficiency. J Ren Nutr. 2012;22:143–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Lin J, Tang Y, Kang Q, Chen A. Curcumin eliminates the inhibitory effect of advanced glycation end-products (AGEs) on gene expression of AGE receptor-1 in hepatic stellate cells in vitro. Lab Invest. 2012.Google Scholar
  17. 17.
    Wang XX, Jiang T, Levi M. Nuclear hormone receptors in diabetic nephropathy. Nat Rev Nephrol. 2010;6:342–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med. 1989;320:1161–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Borch-Johnsen K, Norgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, et al. Is diabetic nephropathy an inherited complication? Kidney Int. 1992;41:719–22.PubMedCrossRefGoogle Scholar
  20. 20.
    •• Bhatt K, Mi QS, Dong Z. microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles. Am J Physiol Renal Physiol. 2011;300:F602–10. Good article to learn about microRNAs and their significance in the kidney.PubMedCrossRefGoogle Scholar
  21. 21.
    Putta S, Lanting L, Sun G, Lawson G, Kato M, Natarajan R. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol. 2012;23:458–69.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, et al. Suppression of microRNA-29 expression by TGF-beta1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol. 2012;23:252–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang Z, Luo X, Ding S, Chen J, Chen T, Chen X, et al. MicroRNA-451 regulates p38 MAPK signaling by targeting of Ywhaz and suppresses the mesangial hypertrophy in early diabetic nephropathy. FEBS Lett. 2012;586:20–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Long J, Wang Y, Wang W, Chang BH, Danesh FR. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J Biol Chem. 2011;286:11837–48.PubMedCrossRefGoogle Scholar
  25. 25.
    Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia. 1998;41:1241–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Zandi-Nejad K, Eddy AA, Glassock RJ, Brenner BM. Why is proteinuria an ominous biomarker of progressive kidney disease? Kidney Int Suppl. 2004;S76–89.Google Scholar
  28. 28.
    Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17:2974–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Cortinovis M, Cattaneo D, Perico N, Remuzzi G. Investigational drugs for diabetic nephropathy. Expert Opin Investig Drugs. 2008;17:1487–500.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    Lane PH, Steffes MW, Fioretto P, Mauer SM. Renal interstitial expansion in insulin-dependent diabetes mellitus. Kidney Int. 1993;43:661–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Fioretto P, Steffes MW, Sutherland DE, Mauer M. Sequential renal biopsies in insulin-dependent diabetic patients: structural factors associated with clinical progression. Kidney Int. 1995;48:1929–35.PubMedCrossRefGoogle Scholar
  33. 33.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.PubMedCrossRefGoogle Scholar
  34. 34.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361:40–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547–53.PubMedCrossRefGoogle Scholar
  38. 38.
    • Balakumar P, Bishnoi HK, Mahadevan N. Telmisartan in the management of diabetic nephropathy: a contemporary view. Curr Diabetes Rev. 2012. Good reading about Telmisartan. Google Scholar
  39. 39.
    Rayner HC, Ross-Gilbertson VL, Walls J. The role of lipids in the pathogenesis of glomerulosclerosis in the rat following subtotal nephrectomy. Eur J Clin Invest. 1990;20:97–104.PubMedCrossRefGoogle Scholar
  40. 40.
    Rovin BH, Tan LC. LDL stimulates mesangial fibronectin production and chemoattractant expression. Kidney Int. 1993;43:218–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Pai R, Kirschenbaum MA, Kamanna VS. Low-density lipoprotein stimulates the expression of macrophage colony-stimulating factor in glomerular mesangial cells. Kidney Int. 1995;48:1254–62.PubMedCrossRefGoogle Scholar
  42. 42.
    Kamanna VS, Pai R, Roh DD, Kirschenbaum MA. Oxidative modification of low-density lipoprotein enhances the murine mesangial cell cytokines associated with monocyte migration, differentiation, and proliferation. Lab Invest. 1996;74:1067–79.PubMedGoogle Scholar
  43. 43.
    Coimbra TM, Janssen U, Grone HJ, Ostendorf T, Kunter U, Schmidt H, et al. Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int. 2000;57:167–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med. 1998;158:998–1004.PubMedCrossRefGoogle Scholar
  45. 45.
    Reisin E, Ebenezer PJ, Liao J, Lee BS, Larroque M, Hu X, et al. Effect of the HMG-CoA reductase inhibitor rosuvastatin on early chronic kidney injury in obese zucker rats fed with an atherogenic diet. Am J Med Sci. 2009;338:301–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Park JK, Muller DN, Mervaala EM, Dechend R, Fiebeler A, Schmidt F, et al. Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effects. Kidney Int. 2000;58:1420–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006;17:2006–16.PubMedCrossRefGoogle Scholar
  48. 48.
    Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54:810–9.PubMedCrossRefGoogle Scholar
  49. 49.
    El Mesallamy HO, Ahmed HH, Bassyouni AA, Ahmed AS. Clinical significance of inflammatory and fibrogenic cytokines in diabetic nephropathy. Clin Biochem. 2012.Google Scholar
  50. 50.
    Nguyen TQ, Tarnow L, Jorsal A, Oliver N, Roestenberg P, Ito Y, 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. 2008;31:1177–82.PubMedCrossRefGoogle Scholar
  51. 51.
    Luo GH, Lu YP, Song J, Yang L, Shi YJ, Li YP. Inhibition of connective tissue growth factor by small interfering RNA prevents renal fibrosis in rats undergoing chronic allograft nephropathy. Transplant Proc. 2008;40:2365–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Adler SG, Schwartz S, Williams ME, Arauz-Pacheco C, Bolton WK, Lee T, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol. 2010;5:1420–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365:327–36.PubMedCrossRefGoogle Scholar
  54. 54.
    Pergola PE, Krauth M, Huff JW, Ferguson DA, Ruiz S, Meyer CJ, et al. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol. 2011;33:469–76.PubMedCrossRefGoogle Scholar
  55. 55.
    • Carter NJ. Pirfenidone: in idiopathic pulmonary fibrosis. Drugs. 2011;71:1721–32. Details therapeutic potential of this novel drug in lung fibrosis that could be relevant to renal fibrosis in near future.PubMedCrossRefGoogle Scholar
  56. 56.
    Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011;20:85–97.PubMedCrossRefGoogle Scholar
  57. 57.
    Mariappan MM. Signaling mechanisms in the regulation of renal matrix metabolism in diabetes. Exp Diabetes Res. 2012;2012:749812.PubMedCrossRefGoogle Scholar
  58. 58.
    Lan HY. TGF-beta/Smad signaling in diabetic nephropathy. Clin Exp Pharmacol Physiol. 2011.Google Scholar
  59. 59.
    Lopez-Hernandez FJ, Lopez-Novoa JM. Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res. 2012;347:141–54.PubMedCrossRefGoogle Scholar
  60. 60.
    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.PubMedCrossRefGoogle Scholar
  61. 61.
    Sharma K, Deelman L, Madesh M, Kurz B, Ciccone E, Siva S, et al. Involvement of transforming growth factor-beta in regulation of calcium transients in diabetic vascular smooth muscle cells. Am J Physiol Renal Physiol. 2003;285:F1258–70.PubMedGoogle Scholar
  62. 62.
    Sharma K, Cook A, Smith M, Valancius C, Inscho EW. TGF-beta impairs renal autoregulation via generation of ROS. Am J Physiol Renal Physiol. 2005;288:F1069–77.PubMedCrossRefGoogle Scholar
  63. 63.
    Kushibiki T, Nagata-Nakajima N, Sugai M, Shimizu A, Tabata Y. Delivery of plasmid DNA expressing small interference RNA for TGF-beta type II receptor by cationized gelatin to prevent interstitial renal fibrosis. J Control Release. 2005;105:318–31.PubMedCrossRefGoogle Scholar
  64. 64.
    Agarwal R, Siva S, Dunn SR, Sharma K. Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels. Am J Kidney Dis. 2002;39:486–92.PubMedCrossRefGoogle Scholar
  65. 65.
    Murphy M, Docherty NG, Griffin B, Howlin J, McArdle E, McMahon R, et al. IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis. J Am Soc Nephrol. 2008;19:1672–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Brennan EP, Morine MJ, Walsh DW, Roxburgh SA, Lindenmeyer MT, Brazil DP, et al. Next-generation sequencing identifies TGF-beta1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy. Biochim Biophys Acta. 2012;1822:589–99.PubMedGoogle Scholar
  67. 67.
    Anliker B, Chun J. Cell surface receptors in lysophospholipid signaling. Semin Cell Dev Biol. 2004;15:457–65.PubMedCrossRefGoogle Scholar
  68. 68.
    Sasagawa T, Suzuki K, Shiota T, Kondo T, Okita M. The significance of plasma lysophospholipids in patients with renal failure on hemodialysis. J Nutr Sci Vitaminol (Tokyo). 1998;44:809–18.CrossRefGoogle Scholar
  69. 69.
    Pradere JP, Klein J, Gres S, Guigne C, Neau E, Valet P, et al. LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol. 2007;18:3110–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, et al. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol. 2010;160:1699–713.PubMedCrossRefGoogle Scholar
  71. 71.
    Fukuda M, Nakamura T, Kataoka K, Nako H, Tokutomi Y, Dong YF, et al. Ezetimibe ameliorates cardiovascular complications and hepatic steatosis in obese and type 2 diabetic db/db mice. J Pharmacol Exp Ther. 2010;335:70–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Tamura Y, Murayama T, Minami M, Matsubara T, Yokode M, Arai H. Ezetimibe Ameliorates Early Diabetic Nephropathy in db/db Mice. J Atheroscler Thromb. 2012.Google Scholar
  73. 73.
    Xu Y, Wan J, Jiang D, Wu X. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells. J Nephrol. 2009;22:403–10.PubMedGoogle Scholar
  74. 74.
    Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003;9:964–8.PubMedCrossRefGoogle Scholar
  75. 75.
    •• Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med. 2012;18:396–404. Present data in support of therapeutic potential of small peptide Alk3.PubMedCrossRefGoogle Scholar
  76. 76.
    •• Tominaga T, Abe H, Ueda O, Goto C, Nakahara K, Murakami T, et al. Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem. 2011;286:20109–16. Present data further supporting the idea of Alk3 as a potential therapeutic target.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang SN, Lapage J, Hirschberg R. Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. J Am Soc Nephrol. 2001;12:2392–9.PubMedGoogle Scholar
  78. 78.
    Borgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O’Sullivan TP, et al. Lipoxin A and benzo-lipoxin A attenuate experimental renal fibrosis. FASEB J. 2011;25:2967–79.PubMedCrossRefGoogle Scholar
  79. 79.
    Flaquer M, Franquesa M, Vidal A, Bolanos N, Torras J, Lloberas N, Herrero-Fresneda I, Grinyo JM, Cruzado JM. Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes. Diabetol. 2012.Google Scholar
  80. 80.
    Komers R. Rho kinase inhibition in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2011;20:77–83.PubMedCrossRefGoogle Scholar
  81. 81.
    Bach LA. Rho kinase inhibition: a new approach for treating diabetic nephropathy? Diabetes. 2008;57:532–3.PubMedCrossRefGoogle Scholar
  82. 82.
    Gil-Bernabe P, D’Alessandro-Gabazza CN, Toda M, Boveda Ruiz D, Miyake Y, Suzuki T, et al. Exogenous activated protein C inhibits the progression of diabetic nephropathy. J Thromb Haemost. 2012;10:337–46.PubMedCrossRefGoogle Scholar
  83. 83.
    Xue M, Dervish S, Harrison LC, Fulcher G, Jackson CJ. Activated protein C inhibits pancreatic islet inflammation, stimulates T regulatory cells and prevents diabetes in NOD mice. J Biol Chem. 2012.Google Scholar
  84. 84.
    Kushiyama T, Oda T, Yamada M, Higashi K, Yamamoto K, Sakurai Y, et al. Alteration in the phenotype of macrophages in the repair of renal interstitial fibrosis in mice. Nephrology (Carlton). 2011;16:522–35.CrossRefGoogle Scholar
  85. 85.
    Vernon MA, Mylonas KJ, Hughes J. Macrophages and renal fibrosis. Semin Nephrol. 2010;30:302–17.PubMedCrossRefGoogle Scholar
  86. 86.
    Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK. Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant. 2008;23:842–52.PubMedCrossRefGoogle Scholar
  87. 87.
    Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS, et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol. 2011;22:317–26.PubMedCrossRefGoogle Scholar
  88. 88.
    Li J, Deane JA, Campanale NV, Bertram JF, Ricardo SD. The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. Stem Cells. 2007;25:697–706.PubMedCrossRefGoogle Scholar
  89. 89.
    Peters V, Schmitt CP. Murine models of diabetic nephropathy. Exp Clin Endocrinol Diabetes. 2012;120:191–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Section of NephrologyYale University School of MedicineNew HavenUSA

Personalised recommendations