Skip to main content

Advertisement

SpringerLink
Log in

Inflammation and diabetic nephropathy

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Ritz E, Rychlik I, Locatelli F, Halimi S: End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 1999, 34:795–808.

    PubMed  CAS  Google Scholar 

  2. Pickup J, Crook M: Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998, 41:1241–1248.

    Article  PubMed  CAS  Google Scholar 

  3. Festa A, D’Agostino R, Howard G, et al.: Chronic subclinical in.ammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000, 101:42–47.

    Google Scholar 

  4. Ford ES: Body mass index, diabetes, and C-reactive protein among US adults. Diabetes 1999, 22:1971–1977.

    Article  CAS  Google Scholar 

  5. Müller S, Martin S, Koenig W, et al.: Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia 2002, 45:805–812.

    Article  PubMed  CAS  Google Scholar 

  6. Temelkova-Kurktschiev T, Henkel E, Koelher C, et al.: Subclinical in.ammation in newly detected type II diabetes and impaired glucose tolerance. Diabetologia 2002, 45:151.

    Article  PubMed  CAS  Google Scholar 

  7. Navarro JF, Mora C, Mac’ia M, Garcc’ia J: Inflammatory parameters are independently associated with urinary albumin excretion in type 2 diabetes mellitus. Am J Kidney Dis 2003, 42:53–61. This clinical study shows that inflammatory parameters, specically C-reactive protein and TNF-α, are direct, significant, and independently associated with urinary albumin excretion in patients with type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  8. Pickup JC, Chusney GC, Thomas SM, Burt D: Plasma interleukin-6, tumor necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci 2000, 67:291–300.

    Article  PubMed  CAS  Google Scholar 

  9. Schmidt MI, Duncan BB, Sharrett AR, et al.: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999, 353:1649–1652.

    Article  PubMed  CAS  Google Scholar 

  10. Pradhan AD, Manson JE, Rifai N, et al.: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327–334.

    Article  PubMed  CAS  Google Scholar 

  11. Festa A, D’Agostino R, Tracey RP, Haffner SM: Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes 2002, 51:1131–1137.

    Article  PubMed  CAS  Google Scholar 

  12. Spranger J, Kroke A, Möhlig M, et al.: Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study. Diabetes 2003, 52:812–817.

    Article  PubMed  CAS  Google Scholar 

  13. Yuan M, Konstantopoulos N, Lee J, et al.: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001, 293:1673–1677.

    Article  PubMed  CAS  Google Scholar 

  14. Freeman DJ, Norrie J, Naveed S, et al.: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001, 103:357–362.

    PubMed  CAS  Google Scholar 

  15. McFarlane SI, Muniyappa R, Francisco R, Stowers JR: Pleiotropic effects of statins: lipid reduction and beyond. J Clin Endocrinol Metab 2002, 87:1451–1458.

    Article  PubMed  CAS  Google Scholar 

  16. Ricote M, Li AC, Wilson TM, et al.: The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998, 391:79–82.

    Article  PubMed  CAS  Google Scholar 

  17. Jiang C, Ting AT, Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998, 391:82–85.

    Article  PubMed  CAS  Google Scholar 

  18. Anderson DC Jr: Pharmacologic prevention or delay of type 2 diabetes mellitus. Ann Pharmacother 2005, 39:102–109.

    PubMed  CAS  Google Scholar 

  19. Crook M: Type 2 diabetes mellitus: a disease of the innate immune system? An update. Diabet Med 2004, 21:203–207.

    Article  PubMed  CAS  Google Scholar 

  20. Maffei M, Fei H, Lee GH, et al.: Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci U S A 1995, 92:6957–6960.

    Article  PubMed  CAS  Google Scholar 

  21. Day CP, Grove J, Daly AK, et al.: Tumor necrosis factor alpha gene promoter polymorphism and decreased insulin resistance. Diabetologia 1998, 41:430–434.

    Article  PubMed  CAS  Google Scholar 

  22. Fern’andez-Real J, Vendrell J, Ricart W, et al.: Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 2000, 49:517–520.

    Article  CAS  Google Scholar 

  23. Utimura R, Fujihara CK, Mattar AL, et al.: Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney Int 2003, 63:209–216.

    Article  PubMed  CAS  Google Scholar 

  24. Wu YG, Lin H, Qi XM, et al.: Prevention of early renal injury by mycophenolate mofetil and its mechanism in experimental diabetes. Int Immunopharmacol 2006, 6:445–453.

    Article  PubMed  CAS  Google Scholar 

  25. Yozai K, Shikata K, Sasaki M, et al.: Methotrexate prevents renal injury in experimental diabetic rats via anti-in.ammatory actions. J Am Soc Nephrol 2005, 16:3326–3338.

    Article  PubMed  CAS  Google Scholar 

  26. Tone A, Shikata K, Sasaki M, et al.: Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats. Diabetologia 2005, 48:2402–2411.

    Article  PubMed  CAS  Google Scholar 

  27. Chow F, Ozols E, Nikolic-Paterson DJ, et al.: Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int 2004, 65:116–128.

    Article  PubMed  CAS  Google Scholar 

  28. Gu L, Tseng SC, Rollins BJ: Monocyte chemoattractant protein-1. Chem Immunol 1999, 72:7–29.

    Article  PubMed  CAS  Google Scholar 

  29. Chow F, Nikolic-Paterson DJ, Ozols E, et al.: Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int 2006, 69:73–80. This experimental study demonstrated that MCP-1-mediated macrophage accumulation and activation is a critical mechanism in the development of early DN.

    Article  PubMed  CAS  Google Scholar 

  30. Tashiro K, Koyanagi I, Saitoh A, et al.: Urinary levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab Anal 2002, 16:1–4.

    Article  PubMed  CAS  Google Scholar 

  31. Chiarelli F, Cipollone F, Mohn A, et al.: Circulating monocyte chemoattractant protein-1 and early development of nephropathy in type 1 diabetes. Diabetes Care 2002, 25:1829–1834.

    Article  PubMed  CAS  Google Scholar 

  32. Morii T, Fujita H, Narita T, et al.: Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J Diabetic Complications 2003, 17:11–15.

    Article  Google Scholar 

  33. Takebayashi K, Matsumoto S, Aso Y, Inukai T: Association between circulating monocyte chemoattractant protein- 1 and urinary albumin excretion in nonobese type 2 diabetic patients. J Diabetes Complications 2006, 20:98–104.

    Article  PubMed  Google Scholar 

  34. Schjoedt KJ, Rossing K, Juhl TR, et al.: Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 2005, 68:2829–2836.

    Article  PubMed  CAS  Google Scholar 

  35. Rossing K, Schjoedt KJ, Smidt UM, et al.: Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. Diabetes Care 2005, 28:2106–2112. This prospective randomized clinical study showed that blockade of aldosterone by spironolactone is associated with beneficial renal effects in both type 1 and type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  36. Fujisawa G, Okada K, Muto S, et al.: Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int 2004, 66:1493–1502.

    Article  PubMed  CAS  Google Scholar 

  37. Han SY, Kim CH, Kim HS, et al.: Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 2006, 17:1362–1372. This experimental study in an animal model of type 2 DN demonstrated that aldosterone induces MCP-1 overproduction in intrinsic renal cells and that spironolactone treatment abolishes aldosteroneinduced MCP-1 production, with renal protective effects associated with anti-inflammatory mechanisms.

    Article  PubMed  CAS  Google Scholar 

  38. Takebayashi K, Matsumoto S, Aso Y, Inukai T: Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrin Metab 2006, 91:2214–2217.

    Article  CAS  Google Scholar 

  39. Stauton DE, Marlin SD, Stratowa D, et al.: Primary structure of ICAM-1 demonstrates interaction between members of the immunoglobulin and integrin supergene families. Cell 1988, 52:925–933.

    Article  Google Scholar 

  40. Matsui H, Suzuki M, Tsukuda R, et al.: Expression of ICAM-1 on glomeruli is associated with progression of diabetic nephropathy in a genetically obese diabetic rat, Wistar fatty. Diabetes Res Clin Pract 1996, 32:1–9.

    Article  PubMed  CAS  Google Scholar 

  41. Coimbra TM, Janssen U, Grone HJ, et al.: Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int 2000, 57:167–182.

    Article  PubMed  CAS  Google Scholar 

  42. Okada S, Shikata K, Matsuda M, et al.: Intercellular adhesion molecule-1 deficient mice are resistant against renal injury after induction of diabetes. Diabetes 2003, 52:2586–2593.

    Article  PubMed  CAS  Google Scholar 

  43. 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. This genetic-deficient mice study demonstrated that ICAM-1 is critically involved in the pathogenesis of DN in both type 1 and type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  44. Clausen P, Jacobsen P, Rossing K, et al.: Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with type1 diabetes mellitus with microalbuminuria and overt nephropathy. Diabet Med 2000, 17:644–649.

    Article  PubMed  CAS  Google Scholar 

  45. Guler S, Cakir B, Demirbas B, et al.: Plasma soluble intercellular adhesion molecule 1 levels are increased in type 2 diabetic patients with nephropathy. Horm Res 2002, 58:67–70.

    Article  PubMed  Google Scholar 

  46. Ulbrich H, Eriksson EE, Lindbom L: Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends Pharmacol Sci 2003, 24:640–647.

    Article  PubMed  CAS  Google Scholar 

  47. Anderson ME, Siahaan TJ: Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: designing peptide and small molecule inhibitors. Peptides 2003, 24:487–501.

    Article  PubMed  CAS  Google Scholar 

  48. Hasegawa G, Nakano K, Sawada M, et al.: Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int 1991, 40:1007–1012.

    PubMed  CAS  Google Scholar 

  49. Hasegawa G, Nakano K, Kondo M: Role of TNF and IL-1 in the development of diabetic nephropathy. Nefrologia 1995, 15:1–4.

    Google Scholar 

  50. Nakamura T, Fukui M, Ebihara I, et al.: mRNA expression of growth factors in glomeruli of diabetic rats. Diabetes 1993, 42:450–456.

    Article  PubMed  CAS  Google Scholar 

  51. Sugimoto H, Shikata K, Wada J, et al.: Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factoralpha and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia 1999, 42:878–886.

    Article  PubMed  CAS  Google Scholar 

  52. Royall JA, Berkow RL, Beckman JS, et al.: Tumor necrosis factor and interleukin 1 increase vascular endothelial permeability. Am J Physiol 1989, 257:L339-L410.

    Google Scholar 

  53. Pfeilschfer J, Pignat W, Vosbeck K, Märki F: Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun 1989, 159:385–394.

    Article  Google Scholar 

  54. Dalla Vestra M, Mussap M, Gallina P, et al.: Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol 2005, 16:S78-S82. This study showed that in patients with type 2 diabetes IL-6 was related to increased GBM width, a cardinal lesion of diabetic glomerulopathy.

    Article  Google Scholar 

  55. Hirano T, Akira S, Taga T, Kishimoto T: Biological and clinical aspect of interleukin 6. Immunol Today 1990, 11:443–449.

    Article  PubMed  CAS  Google Scholar 

  56. Moriwaki Y, Yamamoto T, Shibutani Y, et al.: Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism 2003, 52:605–608.

    Article  PubMed  CAS  Google Scholar 

  57. Nakamura A, Shikata K, Hiramatsu M, et al.: Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care 2005, 28:2890–2895. This work shows that another proinflammatory cytokine, IL-18, is related to nephropathy in type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  58. Navarro J, Milena F, Mora C, et al.: Tumor necrosis factoralpha gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensinconverting enzyme inhibition. Kidney Int 2005, 68(suppl 99):S98-S102. This experimental study in an animal model of diabetes demonstrated that the renal expression of the main proinflammatory cytokines is increased and related to markers of DN.

    Article  Google Scholar 

  59. Baud L, Ardaillou R: Tumor necrosis factor in renal injury. Miner Electrolyte Metab 1995, 21:336–341.

    PubMed  CAS  Google Scholar 

  60. Baud L, Pèrez J, Friedlander G, Ardaillou R: Tumor necrosis factor stimulates prostaglandin production and cyclic AMP levels in rat cultured mesangial cells. FEBS Lett 1998, 239:50–54.

    Article  Google Scholar 

  61. Bertani T, Abbate M, Zoja C, et al.: Tumor necrosis factor induces glomerular damage in rabbit. Am J Pathol 1989, 134:419–430.

    PubMed  CAS  Google Scholar 

  62. McCarthy E, Sharma R, Sharma M, et al.: TNF-alpha increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J Am Soc Nephrol 1998, 9:433–438.

    PubMed  CAS  Google Scholar 

  63. Kalantarinia K, Awas AS, Siragy HM: Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats. Kidney Int 2003, 64:1208–1213.

    Article  PubMed  CAS  Google Scholar 

  64. Ishikura H, Takahashi C, Kanagawa K, et al.: Cytokine regulation of ICAM-1 expression on human renal tubular epithelial cells in vitro. Transplantation 1991, 51:1272–1275.

    Article  PubMed  CAS  Google Scholar 

  65. Dipetrillo K, Coutermarsh B, Gesek FA: Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes. Am J Physiol Renal Physiol 2003, 284:F113-F121.

    PubMed  CAS  Google Scholar 

  66. Navarro JF, Mora C, Rivero A, et al.: Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Am J Kidney Dis 1999, 33:458–463.

    PubMed  CAS  Google Scholar 

  67. Han J, Thompson P, Beutler D: Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 1990, 172:391–394.

    Article  PubMed  CAS  Google Scholar 

  68. Doherty GM, Jensen JC, Alexander HR, et al.: Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 1991, 110:192–198.

    PubMed  CAS  Google Scholar 

  69. Segal R, Dayan M, Zinger H, Mozes E: Suppression of experimental systemic lupus erythematous (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxifylline. Lupus 2001, 10:23–31.

    Article  PubMed  CAS  Google Scholar 

  70. Chen YM, Ng YY, Lin SL, et al.: Pentoxifylline suppresses renal tumour necrosis factor-alpha and ameliorates experimental crescentic glomerulonephritis in rats. Nephrol Dial Transplant 2004, 19:1106–1115.

    Article  PubMed  CAS  Google Scholar 

  71. Chen YM, Chien CT, Hu-Tsai MI, et al.: Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis. Kidney Int 1999, 56:932–943.

    Article  PubMed  CAS  Google Scholar 

  72. Lin SL, Chen YM, Chien CT, et al.: Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol 2002, 13:2916–2929.

    Article  PubMed  CAS  Google Scholar 

  73. DiPetrillo K, Gesek FA: Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am J Nephrol 2004, 24:352–359.

    Article  PubMed  CAS  Google Scholar 

  74. Guerrero-Romero F, Rodr’iguez-Mor’an M, Paniagua-Sierra J, et al.: Pentoxifylline reduces proteinuria in insulin-dependent and non-dependent diabetic patients. Clin Nephrol 1995, 43:116–121.

    PubMed  CAS  Google Scholar 

  75. Navarro J, Mora C, Muros M, et al.: Effects of pentoxifylline administration on urinary N-acetyl-betaglucosaminidase excretion in type 2 diabetic patients: a short-term, prospective, randomised study. Am J Kidney Dis 2003, 42:264–270. This clinical trial showed that pentoxifylline administration to diabetic patients was associated with a significant reduction of glomerular and tubulointerstititial markers of renal injury.

    Article  PubMed  CAS  Google Scholar 

  76. Harmankaya O, Seber S, Yilmaz M: Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients. Ren Fail 2003, 25:465–470.

    Article  PubMed  CAS  Google Scholar 

  77. Navarro JF, Mora C, Muros M, Garc’ia J: Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a shortterm, randomised, controlled trial. J Am Soc Nephrol 2005, 16:2119–2126. This clinical study demonstrated that association of pentoxifylline to blockers of the renin-angiotensin system may offer additional antialbuminuric effects related to modulation of TNF-α.

    Article  PubMed  CAS  Google Scholar 

  78. Chen YM, Lin SL, Chiang WC, et al.: Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int 2006, 69:1410–1415.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Nephrology Service, University Hospital Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010, Santa Cruz de Tenerife, Spain

    Juan F. Navarro MD, FASN

Authors
  1. Carmen Mora MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan F. Navarro MD, FASN
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan F. Navarro MD, FASN.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mora, C., Navarro, J.F. Inflammation and diabetic nephropathy. Curr Diab Rep 6, 463–468 (2006). https://doi.org/10.1007/s11892-006-0080-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-006-0080-1

Keywords

Search

Navigation