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Exp Clin Endocrinol Diabetes 2010; 118(9): 571-576
DOI: 10.1055/s-0030-1255051
Review

© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Mechanisms of Diabetic Nephropathy – Old Buddies and Newcomers Part 1

P. P. Nawroth1 , B. Isermann1
  • 1Department of Medicine I and Clinical Chemistry, University of Heidelberg, INF, Heidelberg, Germany
Further Information

Publication History

received 07.01.2010 first decision 10.03.2010

accepted 11.05.2010

Publication Date:
23 July 2010 (online)

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Abstract

Diabetic nephropathy is the most frequent cause of terminal kidney failure in industrialized countries. In addition, the manifestation of diabetic nephropathy is associated with a poor prognosis for affected patients. Current therapies are based on established pathophysiological models. However, despite reflecting significant progress in our understanding of diabetic nephropathy, the translational efforts fell short their expectations. The current review summarizes recent studies which provided new insights into established mechanisms (part 1) and studies identifying new candidate mechanisms (part 2) underlying diabetic nephropathy.

Key words

diabetes - nephropathy - disease mechanism

References

  • 1 Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions.  Diabetes. 2003;  52 1036-1040
    Search in Google Scholar
  • 2 Jerums G, Premaratne E, Panagiotopoulos S. et al . New and old markers of progression of diabetic nephropathy.  Diabetes Res Clin Pract. 2008;  82 (S 01) S30-S37
    Search in Google Scholar
  • 3 Mauer M, Zinman B, Gardiner R. et al . Renal and retinal effects of enalapril and losartan in type 1 diabetes.  N Engl J Med. 2009;  361 40-51
    Search in Google Scholar
  • 4 Perkins BA, Ficociello LH, Silva KH. et al . Regression of microalbuminuria in type 1 diabetes.  N Engl J Med. 2003;  348 2285-2293
    Search in Google Scholar
  • 5 Hovind P, Tarnow L, Parving HH. Remission and regression of diabetic nephropathy.  Curr Hypertens Rep. 2004;  6 377-382
    Search in Google Scholar
  • 6 Gaede P, Tarnow L, Vedel P. et al . Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria.  Nephrol Dial Transplant. 2004;  19 2784-2788
    Search in Google Scholar
  • 7 Holman RR, Paul SK, Bethel MA. et al . Long-term follow-up after tight control of blood pressure in type 2 diabetes.  N Engl J Med. 2008;  359 1565-1576
    Search in Google Scholar
  • 8 Fioretto P, Caramori ML, Mauer M. The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007.  Diabetologia. 2008;  51 1347-1355
    Search in Google Scholar
  • 9 Dummy EDIC. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study.  JAMA. 2003;  290 2159-2167
    Search in Google Scholar
  • 10 Holman RR, Paul SK, Bethel MA. et al . 10-year follow-up of intensive glucose control in type 2 diabetes.  N Engl J Med. 2008;  359 1577-1589
    Search in Google Scholar
  • 11 Chen HQ, Veluthakal R, Palanivel R. et al . GTP-binding protein-independent potentiation by mastoparan of IL-1beta-induced nitric oxide release from insulin-secreting HIT-T15 cells.  Apoptosis. 2004;  9 145-148
    Search in Google Scholar
  • 12 Ihnat MA, Thorpe JE, Kamat CD. et al . Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling.  Diabetologia. 2007;  50 1523-1531
    Search in Google Scholar
  • 13 El-Osta A, Brasacchio D, Yao D. et al . Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.  J Exp Med. 2008;  205 2409-2417
    Search in Google Scholar
  • 14 Toyoda M, Najafian B, Kim Y. et al . Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy.  Diabetes. 2007;  56 2155-2160
    Search in Google Scholar
  • 15 Fioretto P, Steffes MW, Mauer M. Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria.  Diabetes. 1994;  43 1358-1364
    Search in Google Scholar
  • 16 Caramori ML, Kim Y, Huang C. et al . Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes.  Diabetes. 2002;  51 506-513
    Search in Google Scholar
  • 17 Pagtalunan ME, Miller PL, Jumping-Eagle S. et al . Podocyte loss and progressive glomerular injury in type II diabetes.  J Clin Invest. 1997;  99 342-348
    Search in Google Scholar
  • 18 Langham RG, Kelly DJ, Cox AJ. et al . Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition.  Diabetologia. 2002;  45 1572-1576
    Search in Google Scholar
  • 19 Wharram BL, Goyal M, Wiggins JE. et al . Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.  J Am Soc Nephrol. 2005;  16 2941-2952
    Search in Google Scholar
  • 20 Kalluri R. Proteinuria with and without renal glomerular podocyte effacement.  J Am Soc Nephrol. 2006;  17 2383-2389
    Search in Google Scholar
  • 21 Jarad G, Miner JH. Albuminuria, wherefore art thou?.  J Am Soc Nephrol. 2009;  20 455-457
    Search in Google Scholar
  • 22 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
    Search in Google Scholar
  • 23 Lindenmeyer MT, Kretzler M, Boucherot A. et al . Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.  J Am Soc Nephrol. 2007;  18 1765-1776
    Search in Google Scholar
  • 24 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
    Search in Google Scholar
  • 25 Brownlee M. Biochemistry and molecular cell biology of diabetic complications.  Nature. 2001;  414 813-820
    Search in Google Scholar
  • 26 Hammes HP, Du X, Edelstein D. et al . Benfotiamine blocks 3 major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.  Nat Med. 2003;  9 294-299
    Search in Google Scholar
  • 27 Asaba K, Tojo A, Onozato ML. et al . Effects of NADPH oxidase inhibitor in diabetic nephropathy.  Kidney Int. 2005;  67 1890-1898
    Search in Google Scholar
  • 28 Thallas-Bonke V, Thorpe SR, Coughlan MT. et al . Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway.  Diabetes. 2008;  57 460-469
    Search in Google Scholar
  • 29 Fujii J, Myint T, Okado A. et al . Oxidative stress caused by glycation of Cu,Zn-superoxide dismutase and its effects on intracellular components.  Nephrol Dial Transplant. 1996;  11 (S 05) 34-40
    Search in Google Scholar
  • 30 Bierhaus A, Humpert PM, Morcos M. et al . Understanding RAGE, the receptor for advanced glycation end products.  J Mol Med. 2005;  83 876-886
    Search in Google Scholar
  • 31 Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: where hemodynamics meets metabolism.  Exp Clin Endocrinol Diabetes. 2007;  115 69-84
    Search in Google Scholar
  • 32 Shankar A, Klein R, Klein BE. et al . Association between glycosylated hemoglobin level and 16-year incidence of chronic kidney disease in type 1 diabetes.  Exp Clin Endocrinol Diabetes. 2007;  115 203-206
    Search in Google Scholar
  • 33 Coughlan MT, Thorburn DR, Penfold SA. et al . RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes.  J Am Soc Nephrol. 2009;  20 742-752
    Search in Google Scholar
  • 34 Bohlender JM, Franke S, Stein G. et al . Advanced glycation end products and the kidney.  Am J Physiol Renal Physiol. 2005;  289 F645-F659
    Search in Google Scholar
  • 35 Wendt TM, Tanji N, Guo J. et al . RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.  Am J Pathol. 2003;  162 1123-1137
    Search in Google Scholar
  • 36 Muller-Krebs S, Kihm LP, Zeier B. et al . Renal toxicity mediated by glucose degradation products in a rat model of advanced renal failure.  Eur J Clin Invest. 2008;  38 296-305
    Search in Google Scholar
  • 37 Stopper H, Schinzel R, Sebekova K. et al . Genotoxicity of advanced glycation end products in mammalian cells.  Cancer Lett. 2003;  190 151-156
    Search in Google Scholar
  • 38 Coughlan MT, Thorburn DR, Penfold SA. et al . RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes.  J Am Soc Nephrol. 2009;  20 742-752
    Search in Google Scholar
  • 39 Usui HK, Shikata K, Sasaki M. et al . Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation.  Diabetes. 2007;  56 363-372
    Search in Google Scholar
  • 40 Morcos M, Sayed AA, Bierhaus A. et al . Activation of tubular epithelial cells in diabetic nephropathy.  Diabetes. 2002;  51 3532-3544
    Search in Google Scholar
  • 41 Morcos M, Schlotterer A, Sayed AA. et al . Rosiglitazone reduces angiotensin II and advanced glycation end product-dependent sustained nuclear factor-kappaB activation in cultured human proximal tubular epithelial cells.  Horm Metab Res. 2008;  40 752-759
    Search in Google Scholar
  • 42 Oldfield MD, Bach LA, Forbes JM. et al . Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).  J Clin Invest. 2001;  108 1853-1863
    Search in Google Scholar
  • 43 Lu YL, Jimbu YM, Chen Y. et al . The effects of rosiglitazione on renal artery endothelium in diabetic rats.  Exp Clin Endocrinol Diabetes. 2008;  116 537-540
    Search in Google Scholar
  • 44 Miyata T, Van Ypersele De SC, Ueda Y. et al . Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms.  J Am Soc Nephrol. 2002;  13 2478-2487
    Search in Google Scholar
  • 45 Sun HL, Sun L, Li YY. et al . ACE-inhibitor suppresses the apoptosis induced by endoplasmic reticulum stress in renal tubular in experimental diabetic rats.  Exp Clin Endocrinol Diabetes. 2009;  117 336-344
    Search in Google Scholar
  • 46 Kakoki M, Takahashi N, Jennette JC. et al . Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.  Proc Natl Acad Sci USA. 2004;  101 13302-13305
    Search in Google Scholar
  • 47 Allard J, Buleon M, Cellier E. et al . ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats.  Am J Physiol Renal Physiol. 2007;  293 F1083-F1092
    Search in Google Scholar
  • 48 Bodin S, Chollet C, Goncalves-Mendes N. et al . Kallikrein protects against microalbuminuria in experimental type I diabetes.  Kidney Int. 2009;  76 395-403
    Search in Google Scholar
  • 49 Mann JF, Schmieder RE, McQueen M. 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;  372 547-553
    Search in Google Scholar
  • 50 Ishii H, Jirousek MR, Koya D. et al . Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor.  Science. 1996;  272 728-731
    Search in Google Scholar
  • 51 Meier M, Menne J, Haller H. Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice.  Diabetologia. 2009;  52 765-775
    Search in Google Scholar
  • 52 Meier M, Menne J, Park JK. et al . Deletion of protein kinase C-epsilon signaling pathway induces glomerulosclerosis and tubulointerstitial fibrosis in vivo.  J Am Soc Nephrol. 2007;  18 1190-1198
    Search in Google Scholar
  • 53 Sharma K, Jin Y, Guo J. et al . 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;  45 522-530
    Search in Google Scholar
  • 54 Ziyadeh FN, Hoffman BB, Han DC. et al . 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 USA. 2000;  97 8015-8020
    Search in Google Scholar
  • 55 Ohtomo S, Izuhara Y, Takizawa S. et al . Thiazolidinediones provide better renoprotection than insulin in an obese, hypertensive type II diabetic rat model.  Kidney Int. 2007;  72 1512-1519
    Search in Google Scholar
  • 56 Caramori ML, Fioretto P, Mauer M. Enhancing the predictive value of urinary albumin for diabetic nephropathy.  J Am Soc Nephrol. 2006;  17 339-352
    Search in Google Scholar

Correspondence

Dr. B. Isermann

Universität Heidelberg

Innere Medizin I

INF 410

69120 Heidelberg

Germany

Phone: +49/06221/563 8608

Fax: +49/06221/564 233

Email: berend.isermann@med.uni-heidelberg.de