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  • Review Article
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Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy

Nature Reviews Nephrology volume 7, pages 327–340 (2011)Cite this article

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Abstract

Many lines of evidence, ranging from in vitro experiments and pathological examinations to epidemiological studies, show that inflammation is a cardinal pathogenetic mechanism in diabetic nephropathy. Thus, modulation of inflammatory processes in the setting of diabetes mellitus is a matter of great interest for researchers today. The relationships between inflammation and the development and progression of diabetic nephropathy involve complex molecular networks and processes. This Review, therefore, focuses on key proinflammatory molecules and pathways implicated in the development and progression of diabetic nephropathy: the chemokines CCL2, CX3CL1 and CCL5 (also known as MCP-1, fractalkine and RANTES, respectively); the adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion protein 1, endothelial cell-selective adhesion molecule, E-selectin and α-actinin 4; the transcription factor nuclear factor κB; and the inflammatory cytokines IL-1, IL-6, IL-18 and tumor necrosis factor. Advances in the understanding of the roles that these inflammatory pathways have in the context of diabetic nephropathy will facilitate the discovery of new therapeutic targets. In the next few years, promising new therapeutic strategies based on anti-inflammatory effects could be successfully translated into clinical treatments for diabetic complications, including diabetic nephropathy.

Key Points

  • A wide range of proinflammatory molecules and pathways participate in the pathophysiological spectrum of diabetic nephropathy, including proinflammatory cytokines, chemokines and their receptors, adhesion molecules and transcription factors

  • Inflammatory mechanisms are important in the pathophysiology of diabetic nephropathy and explain how metabolic and hemodynamic abnormalities in patients with diabetes mellitus translate to functional and structural kidney injury

  • IL-18 is strongly associated with diabetic nephropathy; levels of this proinflammatory cytokine might be useful as an early marker of renal dysfunction in patients with type 2 diabetes mellitus

  • Abnormal C-C motif chemokine 2 signaling results in reorganization of the actin cytoskeleton and downregulation of nephrin, causing changes in podocyte structure and function that are associated with albuminuria

  • Endothelial cell-selective adhesion molecule (ESAM) is linked to diabetic nephropathy: high blood levels of glucose decrease ESAM expression, causing tight junction expansion, decreased endothelial fenestration and albuminuria

  • Inhibition of tumor necrosis factor using pentoxifylline improves markers of glomerular and tubulointerstitial injury in patients with diabetic nephropathy; ongoing randomized, controlled clinical trials are investigating the renoprotective effects of this agent

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Figure 1: Overview of inflammatory molecules and signaling pathways in diabetic nephropathy.
Figure 2: TNF signaling cascades have a pivotal role in diabetic nephropathy.
Figure 3: Leukocyte infiltration into the diabetic kidney.
Figure 4: NFκB signaling pathways in diabetic nephropathy.

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References

  1. Cooper, M. E. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44, 1957–1972 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Wolf, G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur. J. Clin. Invest. 34, 785–796 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Martini, S., Eichinger, F., Nair, V. & Kretzler, M. Defining human diabetic nephropathy on the molecular level: integration of transcriptomic profiles with biological knowledge. Rev. Endocr. Metab. Disord. 9, 267–274 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zandi-Nejad, K., Eddy, A. A., Glassock, R. J. & Brenner, B. M. Why is proteinuria an ominous biomarker of progressive kidney disease? Kidney Int. Suppl. 92, S76–S89 (2004).

    Article  CAS  Google Scholar 

  5. Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974–2984 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Vilcek, J. in The Cytokine Handbook 4th edn (eds Thomson, A. W. & Lotze, M. T.) 3–18 (Academic Press, London, 2003).

    Book  Google Scholar 

  7. Alexandraki, K. et al. Inflammatory process in type 2 diabetes. The role of cytokines. Ann. NY Acad. Sci. 1084, 89–117 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Hasegawa, G. et al. Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int. 40, 1007–1012 (1991).

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  10. Nakamura, T. et al. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 42, 450–456 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Sugimoto, H., Shikata, K., Wada, J., Horiuchi, S. & Makino, H. Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-α and inducible oxide synthase in diabetic rat glomeruli. Diabetologia 42, 878–886 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Navarro, J. F. & Mora, C. Role of inflammation in diabetic complications. Nephrol. Dial. Transplant. 20, 2601–2604 (2005).

    Article  PubMed  Google Scholar 

  13. Navarro-González, J. F. & Mora-Fernández, C. The role of inflammatory cytokines in diabetic nephropathy. J. Am. Soc. Nephrol. 19, 433–442 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Sassy-Prigent, C. et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 49, 466–475 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Navarro, J. F. et al. Tumour necrosis factor-α gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition. Kidney Int. Suppl. 99, S98–S102 (2005).

    Article  CAS  Google Scholar 

  16. Navarro, J. F., Milena, F. J., Mora, C., León, C. & García, J. Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am. J. Nephrol. 26, 562–570 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Pfeilschifter, 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. 159, 385–394 (1989).

    Article  CAS  PubMed  Google Scholar 

  18. Pfeilschifter, J. & Mühl, H. Interleukin-1 and tumor necrosis factor potentiate angiotensin II- and calcium ionophore-stimulated prostaglandin E2 synthesis in rat renal mesangial cells. Biochem. Biophys. Res. Commun. 169, 585–595 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Jones, S., Jones, S. & Phillips, A. O. Regulation of renal proximal tubular epithelial cell hyaluronan generation: implications for diabetic nephropathy. Kidney Int. 59, 1739–1749 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Royall, J. A. et al. Tumor necrosis factor and interleukin 1 increase vascular endothelial permeability. Am. J. Physiol. 257, L339–L410 (1989).

    Google Scholar 

  21. Suzuki, D. et al. In situ hybridization of interleukin 6 in diabetic nephropathy. Diabetes 44, 1233–1238 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Coleman, D. L. & Ruef, C. Interleukin-6: an autocrine regulator of mesangial cell growth. Kidney Int. 41, 604–606 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Nosadini, R. et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 49, 476–484 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Dalla Vestra, M. et al. Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J. Am. Soc. Nephrol. 16 (Suppl. 1), S78–S82 (2005).

    Article  PubMed  Google Scholar 

  25. Sekizuka, K. et al. Detection of serum IL-6 in patients with diabetic nephropathy. Nephron 68, 284–285 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Thomson, S. C. et al. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J. Clin. Invest. 107, 217–224 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Melnikov, V. Y. et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J. Clin. Invest. 107, 1145–1152 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Melnikov, V. Y. et al. Neutrophil-independent mechanisms of caspase-1 and IL-18 mediated ischemic acute tubular necrosis in mice. J. Clin. Invest. 110, 1083–1091 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Miyauchi, K., Takiyama, Y., Honjyo, J., Tatano, M. & Haneda, M. Upregulated IL-18 expression in type 2 diabetic subjects with nephropathy: TGF-β1 enhanced IL-18 expression in human renal proximal tubular epithelial cells. Diabetes Res. Clin. Pract. 83, 190–199 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Okamura, H. et al. Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 378, 88–91 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Dai, S. M., Matsuno, H., Nakamura, H., Nishioka, K. & Yudoh, K. Interleukin-18 enhances monocyte tumor necrosis factor α and interleukin-1β production induced by direct contact with T lymphocytes: implications in rheumatoid arthritis. Arthritis Rheum. 50, 432–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Mariño, E. & Cardier, J. E. Differential effects of IL-18 on endothelial cell apoptosis mediated by TNF-α and Fas (CD59). Cytokine 22, 142–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Stuyt, R. J. et al. Selective regulation of intercellular adhesion molecule-1 expression by interleukin-18 and interleukin-12 on human monocytes. Immunology 110, 329–334 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moriwaki, 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 52, 605–608 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Mahmoud, R. A., el-Ezz, S. A. & Hegazy, A. S. Increased serum levels of interleukin-18 in patients with diabetic nephropathy. Ital. J. Biochem. 53, 73–81 (2004).

    PubMed  Google Scholar 

  36. Nakamura, A. et al. Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care 28, 2890–2895 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Wong, C. K. et al. Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy. Clin. Exp. Immunol. 149, 123–131 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Araki, S. et al. Predictive impact of elevated serum level of IL-18 for early renal dysfunction in type 2 diabetes: an observational follow-up study. Diabetologia 50, 867–873 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Fujita, T. et al. Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications. Acta Diabetol. doi:10.1007/s00592-010-0178-4.

  40. Wang, H., Czura, C. J. & Tracey, K. J. in The Cytokine Handbook 4th edn (eds Thomson, A. W. & Lotze, M. T.) 837–860 (Academic Press, London, 2003).

    Google Scholar 

  41. Ortiz, A. et al. Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental and human glomerulonephritis. Adv. Nephrol. Necker Hosp. 24, 53–77 (1995).

    CAS  PubMed  Google Scholar 

  42. Bertani, T. et al. Tumor necrosis factor induces glomerular damage in rabbit. Am. J. Pathol. 134, 419–430 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988).

    CAS  PubMed  Google Scholar 

  44. Baud, L., Pérez, J., Friedlander, G. & Ardaillou, R. Tumor necrosis factor stimulates prostaglandin production and cyclic AMP levels in rat cultured mesangial cells. FEBS Lett. 239, 50–54 (1998).

    Article  Google Scholar 

  45. Wójciak-Stothard, B., Entwistle, A., Garg, R. & Ridley, A. J. Regulation of TNF-α-induced reorganization of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells. J. Cell. Physiol. 176, 150–165 (1998).

    Article  PubMed  Google Scholar 

  46. Koike, N., Takamura, T. & Kaneko, S. Induction of reactive oxygen species from isolated rat glomerli by protein kinase C activation and TNF-α stimulation, and effects of a phosphodiesterase inhibitor. Life Sci. 80, 1721–1728 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. McCarthy, E. T. et al. TNF-α increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J. Am. Soc. Nephrol. 9, 433–438 (1998).

    CAS  PubMed  Google Scholar 

  48. DiPetrillo, K., Coutermarsh, B. & Gesek, F. A. Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes. Am. J. Physiol. Renal Physiol. 284, F113–F121 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. DiPetrillo, K. & Gesek, F. A. Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am. J. Nephrol. 24, 352–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Schreiner, G. F. & Kohan, D. E. Regulation of renal transport processes and hemodynamics by macrophages and lymphocytes. Am. J. Physiol. 258, F761–F767 (1990).

    CAS  PubMed  Google Scholar 

  51. Kalantarinia, K., Awas, A. S. & Siragy, H. M. Urinary and renal interstitial concentrations of TNF-α increase prior to the rise in albuminuria in diabetic rats. Kidney Int. 64, 1208–1213 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Navarro, J. F., Mora, C., Macía, M. & García, J. Inflammatory parameters are independently associated with urinary albumin excretion in type 2 diabetes mellitus. Am. J. Kidney Dis. 42, 53–61 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Navarro, J. F., Mora, C., Muros, M. & García, J. Urinary tumor necrosis factor-α excretion independently correlates with clinical markers of glomerular and tubulointerstitial injury in type 2 diabetic patients. Nephrol. Dial. Transplant. 21, 3428–3434 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Niewczas, M. A. et al. Serum concentrations of markers of TNFα and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin. J. Am. Soc. Nephrol. 4, 62–70 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lin, J., Hu, F. B., Mantzoros, C. & Curhan, G. C. Lipid and inflammatory biomarkers and kidney function decline in type 2 diabetes. Diabetologia 53, 263–267 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Schneider, P. et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB. Immunity 7, 831–836 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Lorz, C. et al. The death ligand TRAIL in diabetic nephropathy. J. Am. Soc. Nephrol. 19, 904–914 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sanchez-Niño, M. D. et al. The MIF receptor CD74 in diabetic podocyte injury. J. Am. Soc. Nephrol. 20, 353–362 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shikata, K. & Makino, H. Role of macrophages in the pathogenesis of diabetic nephropathy. Contrib. Nephrol. 134, 46–54 (2001).

    Article  CAS  Google Scholar 

  60. Tesch, G. H. Role of macrophages in complications of type 2 diabetes. Clin. Exp. Pharmacol. Physiol. 34, 1016–1019 (2007).

    Article  CAS  Google Scholar 

  61. Chow, F., Ozols, E., Nikolic-Paterson, D. J., Atkins, R. C. & Tesch, G. H. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int. 65, 116–128 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Bending, J. J., Lobo-Yeo, A., Vergani, D. & Viberti, G. C. Proteinuria and activated T-lymphocytes in diabetic nephropathy. Diabetes 37, 507–511 (1988).

    Article  CAS  PubMed  Google Scholar 

  63. Salozhin, K. V., Nasonov, E. L. & Sura, W. The cellular immunity indices in diabetic nephropathy [Russian]. Ter. Arkh. 63, 55–58 (1991).

    CAS  PubMed  Google Scholar 

  64. Fardon, N. J., Wilkinson, R. & Thomas, T. H. Abnormalities in primary granule exocytosis in neutrophils from type I diabetic patients with nephropathy. Clin. Sci. (Lond.) 102, 69–75 (2002).

    Article  CAS  Google Scholar 

  65. Takahashi, T. et al. Increased spontaneous adherence of neutrophils from type 2 diabetic patients with overt proteinuria: possible role of the progression of diabetic nephropathy. Diabetes Care 23, 417–418 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Galkina, E. & Ley, K. Leukocyte recruitment and vascular injury in diabetic nephropathy. J. Am. Soc. Nephrol. 17, 368–377 (2006).

    Article  CAS  Google Scholar 

  67. Min, D. et al. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 297, F1229–F1237 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Ruster, C. & Wolf, G. The role of chemokines and chemokine receptors in diabetic nephropathy. Front. Biosci. 13, 944–955 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Panzer, U., Steinmetz, O. M., Stahl, R. A. & Wolf, G. Kidney diseases and chemokines. Curr. Drug Targets 7, 65–80 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Chow, Y. et al. Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice. Diabetologia 50, 471–480 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Chow, Y. et al. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 69, 73–80 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Tarabra, E. 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 54, 2109–2118 (2009).

    Article  CAS  Google Scholar 

  73. Wada, T. et al. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 58, 1492–1498 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Tashiro, K. 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. 16, 1–4 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Morii, T. et al. Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J. Diabetes Complications 17, 11–15 (2003).

    Article  PubMed  Google Scholar 

  76. Lee, E. Y. et al. Monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability. Am. J. Physiol. Renal Physiol. 297, F85–F94 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Janiak, P. et al. Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats. Eur. J. Pharmacol. 534, 271–279 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Mizuno, M. et al. The effect of angiotensin II receptor blockade on an end-stage renal failure model of type 2 diabetes. J. Cardiovasc. Pharmacol. 48, 135–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Amann, B., Tinzmann, R. & Angelkort, B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 26, 2421–2425 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Kitagawa, K. et al. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am. J. Pathol. 165, 237–246 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wada, T. et al. Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J. Am. Soc. Nephrol. 15, 940–948 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Umehara, H. et al. Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler. Thromb. Vasc. Biol. 24, 34–40 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Kikuchi, Y. et al. Fractalkine and its receptor, CX3CR1, upregulation in streptozotocin-induced diabetic kidneys. Nephron Exp. Nephrol. 97, e17–e25 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Kikuchi, Y. et al. Advanced glycation end-product induces fractalkine gene upregulation in normal rat glomeruli. Nephrol. Dial. Transplant. 20, 2690–2696 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Donadelli, R. et al. Protein overload induces fractalkine upregulation in proximal tubular cells through nuclear factor κB- and p38 mitogen-activated protein kinase-dependent pathways. J. Am. Soc. Nephrol. 14, 2436–2446 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Segerer, S. et al. Expression of the fractalkine receptor (CX3CR1) in human kidney diseases. Kidney Int. 62, 488–495 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Appay, V. & Rowland-Jones, S. L. RANTES: a versatile and controversial chemokine. Trends Immunol. 22, 83–87 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Herder, C. et al. Systemic immune mediators and lifestyle changes in the prevention of type 2 diabetes: results from the Finnish Diabetes Prevention Study. Diabetes 55, 2340–2346 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Mezzano, S. et al. NF-κB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol. Dial. Transplant. 19, 2505–2512 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Furuichi, K. et al. Distinct expression of CCR1 and CCR5 in glomerular and interstitial lesions of human glomerular diseases. Am. J. Nephrol. 20, 291–299 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Choi, J. S., Choi, Y. J., Park, S. H., Kang, J. S. & Kang, Y. H. Flavones mitigate tumor necrosis factor-α-induced adhesion molecule upregulation in cultured human endothelial cells: role of nuclear factor-κB. J. Nutr. 134, 1013–1019 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Sumagin, R. & Sarelius, I. H. TNF-α activation of arterioles and venules alters distribution and levels of ICAM-1 and affects leukocyte-endothelial cell interactions. Am. J. Physiol. Heart Circ. Physiol. 291, H2116–H2125 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Sucosky, P., Balachandran, K., Elhammali, A., Jo, H. & Yoganathan, A. P. Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-β1-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 29, 254–260 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Okada, S. et al. Intercellular adhesion molecule-1 deficient mice are resistant against renal injury after induction of diabetes. Diabetes 52, 2586–2593 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Coimbra, T. M. et al. Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int. 57, 167–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Lin, J. et al. Inflammation and progressive nephropathy in type 1 diabetes in the Diabetes Control and Complications Trial. Diabetes Care 31, 2338–2343 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ina, K. et al. Vascular cell adhesion molecule-1 expression in the renal interstitium of diabetic KKAy mice. Diabetes Res. Clin. Pract. 44, 1–8 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Rubio-Guerra, A. F., Vargas-Robles, H., Lozano, J. J. & Escalante-Acosta, B. A. Correlation between circulating adhesion molecule levels and albuminuria in type-2 diabetic hypertensive patients. Kidney Blood Press. Res. 32, 106–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Stehouwer, C. D. et al. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 51, 1157–1165 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Nasdala, I. et al. A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J. Biol. Chem. 277, 16294–16303 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Hara, T., Ishida, T., Cangara, H. M. & Hirata, K. Endothelial cell-selective adhesion molecule regulates albuminuria in diabetic nephropathy. Microvasc. Res. 77, 348–355 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Narumi, S., Onozato, M. L., Tojo, A., Sakamoto, S. & Tamatani, T. Tissue-specific induction of E-selectin in glomeruli is augmented following diabetes mellitus. Nephron 89, 161–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Hirata, K. et al. Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia 41, 185–192 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Soedamah-Muthu, S. S. et al. Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in type 1 diabetic patients. J. Diabetes Complications 20, 188–195 (2006).

    Article  Google Scholar 

  105. Lopes-Virella, M. F. et al. Risk factors related to inflammation and endothelial dysfunction in the DCCT/EDIC cohort and their relationship with nephropathy and macrovascular complications. Diabetes Care 31, 2006–2012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dandapani, S. V. et al. α-Actinin-4 is required for normal podocyte adhesion. J. Biol. Chem. 282, 467–477 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Kimura, M. et al. Expression of alpha-actinin-4 in human diabetic nephropathy. Intern. Med. 47, 1099–1106 (2008).

    Article  PubMed  Google Scholar 

  108. Pieper, G. M. & Riaz-ul-Haq. Activation of nuclear factor-κ-B in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. J. Cardiovasc. Pharmacol. 30, 528–532 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. Yerneni, K. K., Bai, W., Khan, B. V., Medford, R. M. & Natarajan, R. Hyperglycemia-induced activation of nuclear transcription factor κB in vascular smooth muscle cells. Diabetes 48, 855–864 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Gruden, G. et al. Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone. J. Am. Soc. Nephrol. 16, 688–696 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Chuang, L.-Y. & Guh, J.-Y. Extracellular signals and intracellular pathways in diabetic nephropathy. Nephrology 6, 165–172 (2001).

    Article  CAS  Google Scholar 

  112. Iwamoto, M., Mizuiri, S., Arita, M. & Hemmi, H. Nuclear factor-κB activation in diabetic rat kidney: evidence for involvement of P-selectin in diabetic nephropathy. Tohoku J. Exp. Med. 206, 163–171 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Guijarro, C. & Egido, J. Transcription factor-κB (NF-κB) and renal disease. Kidney Int. 59, 415–424 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Han, S. Y. et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J. Am. Soc. Nephrol. 17, 1362–1372 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, F. T. et al. Interactions between angiotensin II and NF-κB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy. J. Am. Soc. Nephrol. 15, 2139–2151 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Schmid, H. et al. Modular activation of nuclear factor-κB transcriptional programs in human diabetic nephropathy. Diabetes 55, 2993–3003 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. Hostetter, T. H. Prevention of end-stage renal disease due to type 2 diabetes. N. Engl. J. Med. 345, 910–912 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Williams, M. E. & Tuttle, K. R. The next generation of diabetic nephropathy therapies: an update. Adv. Chronic Kidney Dis. 12, 212–222 (2005).

    Article  PubMed  Google Scholar 

  119. Ohga, S. et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-κB activation. Am. J. Physiol. Renal Physiol. 292, F1141–F1150 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Ko, G. J. et al. Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. Nephrol. Dial. Transplant. 23, 2750–2760 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Utimura, R. et al. Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney Int. 63, 209–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, Y. et al. Effects of mycophenolate mofetil, valsartan and their combined therapy on preventing podocyte loss in early stage of diabetic nephropathy in rats. Chin. Med. J. (Engl.) 120, 988–995 (2007).

    Article  CAS  Google Scholar 

  123. Rodríguez-Iturbe, B., Quiroz, Y., Shahkarami, A., Li., Z. & Vaziri, N. D. Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat. Kidney Int. 68, 1041–1047 (2005).

    Article  PubMed  Google Scholar 

  124. Moriwaki, Y. et al. Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 44, 215–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. 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. 172, 391–394 (1990).

    Article  CAS  PubMed  Google Scholar 

  126. Doherty, G. M., Jensen, J. C., Alexander, H. R., Buresh, C. M. & Norton, J. A. Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110, 192–198 (1991).

    CAS  PubMed  Google Scholar 

  127. Voisin, L. et al. Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats. Am. J. Physiol. 275, R1412–R1419 (1998).

    CAS  PubMed  Google Scholar 

  128. Cooper, A., Mikhail, A., Lethbridge, M. W., Kemeny, D. M. & Macdougall, I. C. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J. Am. Soc. Nephrol. 15, 1877–1882 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Bolick, D. T., Hatley, M. E., Srinivasan, S., Hedrick, C. C. & Nadler, J. L. Lisofylline, a novel antiinflammatory compound, protects mesangial cells from hyperglycemia- and angiotensin II-mediated extracellular matrix deposition. Endocrinology 144, 5227–5231 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Dávila-Esqueda, M. E., Vertiz-Hernández, A. A. & Martínez-Morales, F. Comparative analysis of the renoprotective effects of pentoxifylline and vitamin E on streptozotocin-induced diabetes mellitus. Ren. Fail. 27, 115–122 (2005).

    Article  PubMed  Google Scholar 

  131. Blagosklonnaia, IaV., Marnedov, R., Kozlov, V. V., Emanuél, V. L. & Kudriashova, M. I. Effect of trental on indices of kidney function in diabetes mellitus [Russian]. Probl. Endokrinol. (Mosk.) 28, 3–8 (1982).

    Google Scholar 

  132. Solerte, S. B. et al. Pentoxifylline, albumin excretion rate and proteinuria in type I and type II diabetic patients with microproteinuria. Results of a short-term randomized study. Acta Diabetol. Lat. 23, 171–177 (1986).

    Article  CAS  PubMed  Google Scholar 

  133. Tripathy, K., Praskash, J., Appaiha, D. & Srivastava, P. K. Pentoxifylline in management of proteinuria in diabetic nephropathy. Nephron 64, 641–642 (1993).

    Article  Google Scholar 

  134. Guerrero-Romero, F. et al. Pentoxifylline reduces proteinuria in insulin-dependent and non insulin-dependent diabetic patients. Clin. Nephrol. 43, 116–121 (1995).

    CAS  PubMed  Google Scholar 

  135. Gorson, D. M. Reduction of macroalbuminuria with pentoxifylline in diabetic nephropathy. Report of three cases. Diabetes Care 21, 2190–2191 (1998).

    Article  CAS  PubMed  Google Scholar 

  136. Navarro, J. F. & Mora, C. Antiproteinuric effect of pentoxifylline in patients with diabetic nephropathy. Diabetes Care 22, 1006–1008 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Navarro, J. F. 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. 33, 458–463 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Navarro, J. F., Mora, C., Muros, M., Maca, M. & Garca, J. Effects of pentoxifylline administration on urinary N-acetyl-β-glucosaminidase excretion in type 2 diabetic patients: a short-term, prospective, randomized study. Am. J. Kidney Dis. 42, 264–270 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. Rodriguez-Morán, M. et al. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: a double-blind, placebo-controlled randomized trial. Clin. Nephrol. 66, 3–10 (2006).

    Article  PubMed  Google Scholar 

  140. Leyva-Jiménez, R. et al. Effect of pentoxifylline on the evolution of diabetic nephropathy [Spanish]. Med. Clin. (Barc.) 132, 772–778 (2009).

    Article  Google Scholar 

  141. Navarro, J. F., Mora, C., Muros, M. & García, J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J. Am. Soc. Nephrol. 16, 2119–2126 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Roozbeh, J. et al. Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. Ren. Fail. 32, 172–178 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. McCormick, B. B. et al. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am. J. Kidney Dis. 52, 454–463 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Navarro-González, J. F. et al. Pentoxifylline for renoprotection in diabetic nephropathy: the PREDIAN study. Rationale and basal results. J. Diabetes Complications doi:10.1016/j.jdiacomp.2010.09.003.

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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-González & Javier García-Pérez

  2. Research Unit, University Hospital Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010, Santa Cruz de Tenerife, Spain

    Carmen Mora-Fernández

  3. Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010, Santa Cruz de Tenerife, Spain

    Mercedes Muros de Fuentes

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  1. Juan F. Navarro-González
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Contributions

J. F. Navarro-González and C. Mora-Fernández contributed equally to all aspects of the article. M. Muros de Fuentes and J. García-Pérez researched data for the article, made substantial contributions to discussion of content as well as reviewing and editing of the manuscript before submission.

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Correspondence to Juan F. Navarro-González.

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Navarro-González, J., Mora-Fernández, C., de Fuentes, M. et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 7, 327–340 (2011). https://doi.org/10.1038/nrneph.2011.51

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