Mechanisms of Diabetic Nephropathy – Old Buddies and Newcomers Part 2

Abstract

The clinical translation of established pathomechanisms of diabetic nephropathy improved the outcome in patients with diabetic nephropathy. However, they fail to halt or even reverse diabetic nephropathy, even though the feasibility of disease reversal has been established. The second part of this review summarizes recent novel insights into the mechanisms of diabetic nephropathy focusing on novel candidate mechanisms of diabetic nephropathy. These studies emphasize a crucial role of endothelial dependent mechanisms, which, however, can not be viewed as independent determinants of diabetic nephropathy. Rather, the endothelial dependent mechanisms act in concert with other cellular systems, establishing an intra-glomerular cross-talk which determines the progression of diabetc nephropathy.

Key words

diabetes - nephropathy - disease mechanisms

References

• 1 Nakagawa T, Kosugi T, Haneda M. et al . Abnormal angiogenesis in diabetic nephropathy.  Diabetes. 2009;  58 1471-1478
• 2 Baelde HJ, Eikmans M, Lappin DW. et al . Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss.  Kidney Int. 2007;  71 637-645
• 3 Eremina V, Baelde HJ, Quaggin SE. Role of the VEGF – a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier.  Nephron Physiol. 2007;  106 32-37
• 4 Ku CH, White KE, Dei CA. et al . Inducible overexpression of sFlt-1 in podocytes ameliorates glomerulopathy in diabetic mice.  Diabetes. 2008;  57 2824-2833
• 5 Nakagawa T. Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease.  Am J Physiol Renal Physiol. 2007;  292 F1665-F1672
• 6 Neugebauer S, Baba T, Watanabe T. Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes.  Diabetes. 2000;  49 500-503
• 7 Zanchi A, Moczulski DK, Hanna LS. et al . Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism.  Kidney Int. 2000;  57 405-413
• 8 Nakagawa T, Sato W, Glushakova O. et al . Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy.  J Am Soc Nephrol. 2007;  18 539-550
• 9 Zhao HJ, Wang S, Cheng H. et al . Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice.  J Am Soc Nephrol. 2006;  17 2664-2669
• 10 Nakagawa T, Sato W, Sautin YY. et al . Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy.  J Am Soc Nephrol. 2006;  17 736-745
• 11 Davis B, Dei CA, Long DA. et al . Podocyte-specific expression of angiopoetin-2 causes proteinuria and apoptosis of glomerular endothelia.  J Am Soc Nephrol. 2007;  18 2320-2329
• 12 Isermann B, Vinnikov IA, Madhusudhan T. et al . Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.  Nat Med. 2007;  13 1349-1358
• 13 Gilbert RE, Marsden PA. Activated protein C and diabetic nephropathy.  N Engl J Med. 2008;  358 1628-1630
• 14 Isermann B, Hendrickson SB, Zogg M. et al . Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis.  J Clin Invest. 2001;  108 537-546
• 15 Weiler H, Isermann BH. Thrombomodulin.  J Thromb Haemost. 2003;  1 1515-1524
• 16 Fujiwara Y, Tagami S, Kawakami Y. Circulating thrombomodulin and hematological alterations in type 2 diabetic patients with retinopathy.  J Atheroscler Thromb. 1998;  5 21-28
• 17 Borcea V, Morcos M, Isermann B. et al . Influence of ramipril on the course of plasma thrombomodulin in patients with diabetes mellitus.  Vasa. 1999;  28 172-180
• 18 Matsumoto K, Yano Y, Gabazza EC. et al . Inverse correlation between activated protein C generation and carotid atherosclerosis in Type 2 diabetic patients.  Diabet Med. 2007;  24 1322-1328
• 19 Isermann B, Sood R, Pawlinski R. et al . The thrombomodulin-protein C system is essential for the maintenance of pregnancy.  Nat Med. 2003;  9 331-337
• 20 Glaser CB, Morser J, Clarke JH. et al . Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.  J Clin Invest. 1992;  90 2565-2573
• 21 Ceriello A, Esposito K, Ihnat M. et al . Simultaneous control of hyperglycemia and oxidative stress normalizes enhanced thrombin generation in type 1 diabetes.  J Thromb Haemost. 2009;  7 1228-1230
• 22 Gupta A, Williams MD, Macias WL. et al . Activated Protein C and Acute Kidney Injury: Selective Targeting of PAR-1.  Curr Drug Targets. 2009; 
• 23 Kaneider NC, Leger AJ, Agarwal A. et al . ‘Role reversal’ for the receptor PAR1 in sepsis-induced vascular damage.  Nat Immunol. 2007;  8 1303-1312
• 24 Lassila M, Seah KK, Allen TJ. et al . Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products.  J Am Soc Nephrol. 2004;  15 2125-2138
• 25 Gaede P, Lund-Andersen H, Parving HH. et al . Effect of a multifactorial intervention on mortality in type 2 diabetes.  N Engl J Med. 2008;  358 580-591
• 26 Proctor G, Jiang T, Iwahashi M. et al . Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes.  Diabetes. 2006;  55 2502-2509
• 27 Komers R, Lindsley JN, Oyama TT. et al . Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats.  Clin Exp Pharmacol Physiol. 2007;  34 36-41
• 28 Abrahamian H, Endler G, Exner M. et al . Association of low-grade inflammation with nephropathy in type 2 diabetic patients: role of elevated CRP-levels and 2 different gene-polymorphisms of proinflammatory cytokines.  Exp Clin Endocrinol Diabetes. 2007;  115 38-41
• 29 Galkina E, Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy.  J Am Soc Nephrol. 2006;  17 368-377
• 30 Chow FY, Nikolic-Paterson DJ, Ozols E. et al . Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice.  J Am Soc Nephrol. 2005;  16 1711-1722
• 31 Xiao X, Ma B, Dong B. et al . Cellular and humoral immune responses in the early stages of diabetic nephropathy in NOD mice.  J Autoimmun. 2009;  32 85-93
• 32 Moriya R, Manivel JC, Mauer M. Juxtaglomerular apparatus T-cell infiltration affects glomerular structure in Type 1 diabetic patients.  Diabetologia. 2004;  47 82-88
• 33 Sato W, Kosugi T, Zhang L. et al . The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy.  Lab Invest. 2008;  88 949-961
• 34 Tarabra E, Giunti S, Barutta F. et al . Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes.  Diabetes. 2009;  58 2109-2118
• 35 Pezzolesi MG, Katavetin P, Kure M. et al . Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy.  Diabetes. 2009;  58 2698-2702
• 36 Russo LM, Sandoval RM, Campos SB. et al . Impaired tubular uptake explains albuminuria in early diabetic nephropathy.  J Am Soc Nephrol. 2009;  20 489-494
• 37 Kato M, Zhang J, Wang M. et al . 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. 2007;  104 3432-3437
• 38 Mahimainathan L, Das F, Venkatesan B. et al . Mesangial cell hypertrophy by high glucose is mediated by downregulation of the tumor suppressor PTEN.  Diabetes. 2006;  55 2115-2125
• 39 Zhang Z, Peng H, Chen J. et al . MicroRNA-21 protects from mesangial cell proliferation induced by diabetic nephropathy in db/db mice.  FEBS Lett. 2009;  583 2009-2014
• 40 Kato M, Putta S, Wang M. et al . TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN.  Nat Cell Biol. 2009;  11 881-889
• 41 Dai C, Stolz DB, Kiss LP. et al . Wnt/beta-catenin signalling promotes podocyte dysfunction and albuminuria.  J Am Soc Nephrol. 2009;  20 1997-2008
• 42 Lee SH, Kim MH, Han HJ. Arachidonic acid potentiates hypoxia-induced VEGF expression in mouse embryonic stem cells: involvement of Notch, Wnt, and HIF-1alpha.  Am J Physiol Cell Physiol. 2009;  297 C207-C216
• 43 Wang SN, Lapage J, Hirschberg R. Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy.  J Am Soc Nephrol. 2001;  12 2392-2399
• 44 Dolan V, Murphy M, Sadlier D. et al . Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy.  Am J Kidney Dis. 2005;  45 1034-1039
• 45 Wang S, Chen Q, Simon TC. et al . Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.  Kidney Int. 2003;  63 2037-2049
• 46 Walsh DW, Roxburgh SA, McGettigan P. et al . Co-regulation of Gremlin and Notch signalling in diabetic nephropathy.  Biochim Biophys Acta. 2008;  1782 10-21
• 47 Lee SH, Kim MH, Han HJ. Arachidonic acid potentiates hypoxia-induced VEGF expression in mouse embryonic stem cells: involvement of Notch, Wnt, and HIF-1alpha.  Am J Physiol Cell Physiol. 2009;  297 C207-C216
• 48 Niranjan T, Bielesz B, Gruenwald A. et al . The Notch pathway in podocytes plays a role in the development of glomerular disease.  Nat Med. 2008;  14 290-298
• 49 Walsh DW, Roxburgh SA, McGettigan P. et al . Co-regulation of Gremlin and Notch signalling in diabetic nephropathy.  Biochim Biophys Acta. 2008;  1782 10-21

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