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Inflammation in diabetic nephropathy: moving toward clinical biomarkers and targets for treatment

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Abstract

Diabetic nephropathy (DN) is a leading cause of end stage renal failure and there is an urgent need to identify new clinical biomarkers and targets for treatment to effectively prevent and slow the progression of the complication. Many lines of evidence show that inflammation is a cardinal pathogenetic mechanism in DN. Studies in animal models of experimental diabetes have demonstrated that there is a low-grade inflammation in the diabetic kidney. Both pharmacological and genetic strategies targeting inflammatory molecules have been shown to be beneficial in experimental DN. In vitro studies have cast light on the cellular mechanisms whereby diabetes triggers inflammation and in turn inflammation magnifies the kidney injury. Translation of this basic science knowledge into potential practical clinical applications is matter of great interest for researchers today. This review focuses on key pro-inflammatory systems implicated in the development of DN: the tumor necrosis factor(TNF)-α/TNF-α receptor system, the monocyte chemoattractant protein-1/CC-chemokine receptor-2 system, and the Endocannabinoid system that have been selected as they appear particularly promising for future clinical applications.

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References

  1. American Diabetes Association, Standards of medical care in diabetes. Diabetes Care 37(suppl.1), S42–S44 (2014)

    Google Scholar 

  2. L.A. Stevens, T. Greene, A.S. Levey, Surrogate end points for clinical trials of kidney disease progression. Clin. J. Am. Soc. Nephrol. 1, 874–884 (2006)

    PubMed  Google Scholar 

  3. H.J. Lambers Heerspink, D. de Zeeuw, Debate: PRO position. Should microalbuminuria ever be considered as a renal endpoint in any clinical trial? Am. J. Nephrol. 31, 458–461 (2010)

    PubMed  Google Scholar 

  4. R.J. Glassock, Debate: CON position. Should microalbuminuria ever be considered as a renal endpoint in any clinical trial? Am. J. Nephrol. 31, 462–465 (2010)

    PubMed  Google Scholar 

  5. R.J. Macisaac, G. Jerums, Diabetic kidney disease with and without albuminuria. Curr. Opin. Nephrol. Hypertens. 20, 246–257 (2011)

    CAS  PubMed  Google Scholar 

  6. G. Penno, A. Solini, E. Bonora, C. Fondelli, E. Orsi, G. Zerbini, R. Trevisan, M. Vedovato, G. Gruden, F. Cavalot, M. Cignarelli, L. Laviola, S. Morano, A. Nicolucci, G. Pugliese, Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. J. Hypertens. 29, 1802–1809 (2011)

    CAS  PubMed  Google Scholar 

  7. DCCT. The effect of intensive treatment of diabetes on the development and progression of long term complications in the insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–86 (1993)

  8. UK Prospective Diabetes Study, UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet 12, 837–853 (1998)

    Google Scholar 

  9. E.J. Lewis, L.G. Hunsicker, R.P. Bain, R.D. Rohde, The effect of ACE inhibition on diabetic nephropathy. N. Engl. J. Med. 329, 1456–1462 (1993)

    CAS  PubMed  Google Scholar 

  10. A.S. Krolewski, M. Canessa, J.H. Warram, L.M. Laffel, A.R. Christlieb, W.C. Knowler, L.I. Rand, Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N. Engl. J. Med. 318, 140 (1988)

    CAS  PubMed  Google Scholar 

  11. P. Gaede, P. Vedel, H.H. Parving, O. Pedersen, Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 20(353), 617–622 (1999)

    Google Scholar 

  12. T. Furuta, T. Saito, T. Ootaka, J. Soma, K. Obara, K. Abe, K. Yoshinaga, The role of macrophages in diabetic glomerulosclerosis. Am. J. Kidney Dis. 21, 480–485 (1993)

    CAS  PubMed  Google Scholar 

  13. C. Viedt, S.R. Orth, Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does it more than simply attract monocytes? Nephrol. Dial. Transplant. 17, 2043–2047 (2002)

    CAS  PubMed  Google Scholar 

  14. C. Sassy-Prigent, D. Heudes, C. Mandet, M.F. Bélair, O. Michel, B. Perdereau, J. Bariéty, P. Bruneval, Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 49, 466–475 (2000)

    CAS  PubMed  Google Scholar 

  15. H. Sugimoto, K. Shikata, K. Hirata, K. Akiyama, M. Matsuda, M. Kushiro, Y. Shikata, N. Miyatake, M. Miyasaka, H. Makino, Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1 upregulation. Diabetes 46, 2075–2081 (1997)

    CAS  PubMed  Google Scholar 

  16. S. Kato, V.A. Luyckx, M. Ots, K.W. Lee, F. Ziai, J.L. Troy, B.M. Brenner, H.S. MacKenzie, Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int. 56, 1037–1048 (1999)

    CAS  PubMed  Google Scholar 

  17. S. Okada, K. Shikata, M. Matsuda, D. Ogawa, H. Usui, Y. Kido, R. Nagase, J. Wada, Y. Shikata, H. Makino, Intercellular adhesion molecule-1—deficient mice are resistant against renal injury after induction of diabetes. Diabetes 52, 2586–2593 (2003)

    CAS  PubMed  Google Scholar 

  18. F.Y. Chow, D.J. Nikolic-Paterson, E. Ozols, R.C. Atkins, B.J. Rollin, G.H. Tesch, Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 69, 73–80 (2006)

    CAS  PubMed  Google Scholar 

  19. H. You, T. Gao, T.K. Cooper, W. Brian Reeves, A.S. Awad, Macrophages directly mediate diabetic renal injury. Am. J. Physiol. Renal Physiol. 305, F1719–F1727 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. I.Z. Pawluczyk, K.P. Harris, Macrophages promote prosclerotic responses in cultured rat mesangial cells: a mechanism for the initiation of glomerulosclerosis. J. Am. Soc. Nephrol. 8, 1525–1536 (1997)

    CAS  PubMed  Google Scholar 

  21. Y. Ikezumi, T. Suzuki, T. Karasawa, H. Kawachi, D.J. Nikolic-Paterson, M. Uchiyama, Activated macrophages down-regulate podocyte nephrin and podocin expression via stress-activated protein kinases. Biochem. Biophys. Res. Commun. 376, 706–711 (2008)

    CAS  PubMed  Google Scholar 

  22. C.W. Park, J.H. Kim, J.H. Lee, Y.S. Kim, H.J. Ahn, Y.S. Shin, S.Y. Kim, E.J. Choi, Y.S. Chang, B.K. Bang, High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-kappa B-dependent. Diabetologia 43, 1544–1553 (2000)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  24. F.Y. Chow, D.J. Nikolic-Paterson, F.Y. Ma, E. Ozols, B.J. Rollins, G.H. Tesch, 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)

    CAS  PubMed  Google Scholar 

  25. S.D. Ricardo, H. van Goor, A.A. Eddy, Macrophage diversity in renal injury and repair. J. Clin. Invest. 118, 3522–3530 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. D. Zheng, Y. Wang, Q. Cao, V.W. Lee, G. Zheng, Y. Sun, T.K. Tan, Y. Wang, S.I. Alexander, D.C. Harris, Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus. Nephron Exp. Nephrol. 118, e87–e99 (2011)

    PubMed  Google Scholar 

  27. P.J. Naudé, J.A. den Boer, P.G. Luiten, U.L. Eisel, Tumor necrosis factor receptor cross-talk. FEBS J. 278, 888–898 (2011)

    PubMed  Google Scholar 

  28. A. Ortiz, C. Bustos, J. Alonso, R. Alcázar, M.J. López-Armada, J.J. Plaza, E. González, J. Egido, 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 

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

    CAS  PubMed  Google Scholar 

  30. J.J. Boyle, P.L. Weissberg, M.R. Bennett, Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler. Thromb. Vasc. Biol. 23, 1553–1558 (2003)

    CAS  PubMed  Google Scholar 

  31. J.A. McKenzie, A.J. Ridley, Roles of Rho/ROCK and MLCK in TNF-alpha-induced changes in endothelial morphology and permeability. J. Cell Physiol. 213, 221–228 (2007)

    CAS  PubMed  Google Scholar 

  32. H.H. Radeke, B. Meier, N. Topley, J. Flöge, G.G. Habermehl, K. Resch, Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production mesangial cells. Kidney Int. 37, 767–775 (1990)

    CAS  PubMed  Google Scholar 

  33. G. Hasegawa, K. Nakano, M. Sawada, K. Uno, Y. Shibayama, K. Ienaga, M. Kondo, Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int. 40, 1007–1012 (1991)

    CAS  PubMed  Google Scholar 

  34. L. Baud, J.P. Oudinet, M. Bens, L. Noe, M.N. Peraldi, E. Rondeau, J. Etienne, R. Ardaillou, Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 35, 1111–1118 (1989)

    CAS  PubMed  Google Scholar 

  35. A.K. Hughes, P.K. Stricklett, D.E. Kohan, Shiga toxin-1 regulation of cytokine production by human glomerular epithelial cells. Nephron. 88, 14–23 (2001)

    CAS  PubMed  Google Scholar 

  36. A.M. Jevnikar, D.C. Brennan, G.G. Singer, J.E. Heng, W. Maslinski, R.P. Wuthrich, L.H. Glimcher, V.E. Kelley, Stimulated kidney tubular epithelial cells express membrane associated and secreted TNF-α. Kidney Int. 40, 203–211 (1991)

    CAS  PubMed  Google Scholar 

  37. X.H. Wu, S.M. Huang, W.X. Fan, W.X. Tang, H.Y. Qiu, Influence of high glucose and mannose binding lectin complement pathway activation to IL-6 and TNF-alpha’s expression by human renal glomerular endothelial cells. Sichuan Da Xue Xue Bao Yi Xue Ban. 42, 90–94. Chinese. (2011)

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

    CAS  PubMed  Google Scholar 

  39. K. Omote, T. Gohda, M. Murakoshi, Y. Sasaki, S. Kazuno, T. Fujimura, M. Ishizaka, Y. Sonoda, Y. Tomino, Role of the TNF pathway in the progression of diabetic nephropathy in KK-Ay mice. Am. J. Physiol. Renal Physiol. 306, F1335–F1347 (2014)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Y. Moriwaki, T. Inokuchi, A. Yamamoto, T. Ka, Z. Tsutsumi, S. Takahashi, T. Yamamoto, Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 44, 215–218 (2007)

    CAS  PubMed  Google Scholar 

  42. R. Pai, B. Bassa, M.A. Kirschenbaum, V.S. Kamanna, TNF-alpha stimulates monocyte adhesion to glomerular mesangial cells. The role of intercellular adhesion molecule-1 gene expression and protein kinases. J. Immunol. 156, 2571–2579 (1996)

    CAS  PubMed  Google Scholar 

  43. S.K. Lee, J.Y. Park, S.J. Chung, W.S. Yang, S.B. Kim, S.K. Park, J.S. Park, Chemokines, osteopontin, ICAM-1 gene expression in cultured rat mesangial cells. J. Korean Med. Sci. 13, 165–170 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. A. Marfaing-Koka, O. Devergne, G. Gorgone, A. Portier, T.J. Schall, P. Galanaud, D. Emilie, Regulation of the production of the RANTES chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and inhibition by IL-4 and IL-13. J. Immunol. 154, 1870–1878 (1995)

    CAS  PubMed  Google Scholar 

  45. V.S. Kamanna, R. Pai, B. Bassa, M.A. Kirschenbaum, Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase. Biochim. Biophys. Acta 1313, 161–172 (1996)

    PubMed  Google Scholar 

  46. G. Wolf, S. Aberle, F. Thaiss, P.J. Nelson, A.M. Krensky, E.G. Neilson, R.A. Stahl, TNF alpha induces expression of the chemoattractant cytokine RANTES in cultured mouse mesangial cells. Kidney Int. 44, 795–804 (1993)

    CAS  PubMed  Google Scholar 

  47. C. Zoja, J.M. Wang, S. Bettoni, M. Sironi, D. Renzi, F. Chiaffarino, H.E. Abboud, J. Van Damme, A. Mantovani, G. Remuzzi, Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. Am. J. Pathol. 138, 991–1003 (1991)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. A. Taubitz, M. Schwarz, N. Eltrich, M.T. Lindenmeyer, V. Vielhaue, Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice. PLoS One 8, e68167 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Z. Hruby, K.F. Beck, Cytotoxic effect of autocrine and macrophage derived nitric oxide on cultured rat mesangial cells. Clin. Exp. Immunol. 107, 76–82 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. I.Z. Pawluczyk, K.P. Harris, Cytokine interactions promote synergistic fibronectin accumulation by mesangial cells. Kidney Int. 54, 62–70 (1998)

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. K. Yamauchi, Y. Takano, A. Kasai, K. Hayakawa, N. Hiramatsu, N. Enomoto, J. Yao, M. Kitamura, Screening and identification of substances that regulate nephrin gene expression using engineered reporter podocytes. Kidney Int. 70, 892–900 (2006)

    CAS  PubMed  Google Scholar 

  53. Y. Takano, K. Yamauchi, K. Hayakawa, N. Hiramatsu, A. Kasai, M. Okamura, M. Yokouchi, A. Shitamura, J. Yao, M. Kitamura, Transcriptional suppression of nephrin in podocytes by macrophages: role of inflammatory cytokines and involvement of the PI3K/Akt pathway. FEBS Lett. 581, 421–426 (2007)

    CAS  PubMed  Google Scholar 

  54. S. Doublier, V. Ruotsalainen, G. Salvidio, E. Lupia, L. Biancone, P.G. Conaldi, P. Reponen, K. Tryggvason, G. Camussi, Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am. J. Pathol. 158, 1723–1731 (2001)

    CAS  PubMed  PubMed Central  Google Scholar 

  55. S.B. Koukouritaki, E.A. Vardaki, E.A. Papakonstanti, E. Lianos, C. Stournaras, D.S. Emmanouel, TNF-alpha induces actin cytoskeleton reorganization in glomerular epithelial cells involving tyrosine phosphorylation of paxillin and focal adhesion kinase. Mol. Med. 5, 382–392 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. T. Tejada, P. Catanuto, A. Ijaz, J.V. Santos, X. Xia, P. Sanchez, N. Sanabria, O. Lenz, S.J. Elliot, A. Fornoni, Failure to phosphorylate AKT in podocytes from mice with early diabetic nephropathy promotes cell death. Kidney Int. 73, 1385–1393 (2008)

    CAS  PubMed  Google Scholar 

  57. J. Han, P. Thompson, B. Beutler, Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signalling pathway. J. Exp. Med. 172, 393–394 (1990)

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. M.C. Thomas, Emerging drugs for managing kidney disease in patients with diabetes. Expert Opin. Emerging Drugs. 18, 55–70 (2013)

  60. B.B. McCormick, A. Sydor, A. Akbari, D. Fergusson, S. Doucette, G. Knoll, The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am. J. Kidney Dis. 52, 454–463 (2008)

    CAS  PubMed  Google Scholar 

  61. J.F. Navarro-González, C. Mora-Fernández, M. Muros de Fuentes, M.L. Méndez, E. Gallego, M. Macía, N. Del Castillo, A. Rivero, N. Del Castillo, M.A. Getino, P. García, A. Jarque, J. García, Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J. Am. Soc. Nephrol. (2014). doi:10.1681/ASN.2014010012

    PubMed  Google Scholar 

  62. M.H. Bemelmans, L.J. van Tits, W.A. Buurman, Tumor necrosis factor: function, release and clearance. Crit. Rev. Immunol. 16, 1–11 (1996)

  63. Y. Moriwaki, T. Yamamoto, Y. Shibutani, E. Aoki, Z. Tsutsumi, S. Takahashi, H. Okamura, M. Koga, M. Fukuchi, T. Hada, Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism. 53, 605–608 (2003)

    Google Scholar 

  64. J.F. Navarro, C. Mora, M. Muros, J. García, Urinary tumour necrosis factor-α excretion independently correlates with clinical markers of glomerular and tubulointerstitial injury in type 2 diabetic patients. Nephrol. Dial. Transplant. 21(12), 3428–3434 (2006)

    CAS  PubMed  Google Scholar 

  65. G. Gruden, F. Barutta, N. Chaturvedi, C. Schalkwijk, C.D. Stehouwer, S. Pinach, M. Manzo, M. Loiacono, M. Tricarico, G. Mengozzi, D.R. Witte, J.H. Fuller, P.C. Perin, G. Bruno, NH2-terminal probrain natriuretic peptide is associated with diabetes complications in the EURODIAB Prospective Complications Study: the role of tumor necrosis factor-α. Diabetes Care 35, 1931–1936 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. J. Lin, F.B. Hu, E.B. Rimm, N. Rifai, G.C. Curhan, The association of serum lipids and inflammatory biomarkers with renal function in men with type II diabetes mellitus. Kidney Int. 69, 336–342 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  67. M.A. Niewczas, L.H. Ficociello, A.C. Johnson, W. Walker, E.T. Rosolowsky, B. Roshan, J.H. Warram, A.S. Krolewski, 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)

    CAS  PubMed  PubMed Central  Google Scholar 

  68. T. Gohda, M.A. Niewczas, L.H. Ficociello, W.H. Walker, J. Skupien, F. Rosetti, X. Cullere, A.C. Johnson, G. Crabtree, A.M. Smiles, T.N. Mayadas, J.H. Warram, A.S. Krolewski, Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J. Am. Soc. Nephrol. 23, 516–524 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. M.A. Niewczas, T. Gohda, J. Skupien, A.M. Smiles, W.H. Walker, F. Rosetti, X. Cullere, J.H. Eckfeldt, A. Doria, T.N. Mayadas, J.H. Warram, A.S. Krolewski, Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J. Am. Soc. Nephrol. 23, 507–515 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. M.F. Lopes-Virella, N.L. Baker, K.J. Hunt, P.A. Cleary, R. Klein, G. Virella, DCCT/EDIC Research Group.: Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes Care 36, 2317–2323 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  71. C. Forsblom, J. Moran, V. Harjutsalo, T. Loughman, J. Wadén, N. Tolonen, L. Thorn, M. Saraheimo, D. Gordin, P.H. Groop, M.C. Thomas, on behalf of the FinnDiane Study Group, Added value of soluble Tumor Necrosis Factor Alpha Receptor-1 as a biomarker of ESRD risk. Diabetes Care (2014). doi:10.2337/dc14-0225

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  73. F.T. Lee, Z. Cao, D.M. Long, S. Panagiotopoulos, G. Jerums, M.E. Cooper, J.M. Forbes, Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy. J. Am. Soc. Nephrol. 15, 2139–2151 (2004)

    CAS  PubMed  Google Scholar 

  74. S. Mezzano, A. Droguett, M.E. Burgos, L.G. Ardiles, C.A. Flores, C.A. Aros, I. Caorsi, C.P. Vío, M. Ruiz-Ortega, J. Egido, Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int. Suppl. 86, S64–S70 (2003)

    CAS  PubMed  Google Scholar 

  75. E. Tarabra, S. Giunti, F. Barutta, G. Salvidio, D. Burt, G. Deferrari, R. Gambino, D. Vergola, S. Pinach, P.C. Perin, G. Camussi, G. Gruden, Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes 58, 2109–2118 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  76. N. Banba, T. Nakamura, M. Matsumura, H. Kuroda, Y. Hattori, K. Kasai, Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. Kidney Int. 58, 684–690 (2000)

    CAS  PubMed  Google Scholar 

  77. H. Ha, M.R. Yu, Y.J. Choi, M. Kitamura, H.B. Lee, Role of high glucose–induced nuclear factor-B activation in monocyte chemoattractant protein-1 expression by mesangial cells. J. Am. Soc. Nephrol. 13, 894–902 (2002)

    CAS  PubMed  Google Scholar 

  78. M. Naito, A. Shenoy, I. Aoyama, J.S. Koopmeiners, R. Komers, H.W. Schnaper, K. Bomsztyk, High ambient glucose augments angiotensin ii-induced proinflammatory gene mrNA expression in human mesangial cells: effects of valsartan and simvastatin. Am. J. Nephrol. 30, 99–111 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. C.G. Ihm, J.K. Park, S.P. Hong, T.W. Lee, B.S. Cho, M.J. Kim, D.R. Cha, H. Ha, A high glucose concentration stimulates the expression of monocyte chemotactic peptide 1 in human mesangial cells. Nephron. 79, 33–37 (1998)

    CAS  PubMed  Google Scholar 

  80. S.Y. Han, G.A. So, Y.H. Jee, K.H. Han, Y.S. Kang, H.K. Kim, S.W. Kang, D.S. Han, J.Y. Han, D.R. Cha, Effect of retinoic acid in experimental diabetic nephropathy. Immunol. Cell Biol. 82, 568–576 (2004)

    CAS  PubMed  Google Scholar 

  81. E.Y. Lee, C.H. Chung, C.C. Khoury, T.K. Yeo, P.E. Pyagay, A. Wang, S. Chen, The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-beta, increases podocyte motility and albumin permeability. Am. J. Physiol. Renal Physiol. 297, F85–F94 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  82. T. Matsui, S. Yamagishi, M. Takeuchi, S. Ueda, K. Fukami, S. Okuda, Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferatoractivated receptor-gamma activation. Biochem. Biophys. Res. Commun. 385, 269–272 (2009)

    CAS  PubMed  Google Scholar 

  83. T. Matsui, S. Yamagishi, S. Ueda, K. Nakamura, T. Imaizumi, M. Takeuchi, H. Inoue, Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation. J. Int. Med. Res. 35, 482–489 (2007)

    CAS  PubMed  Google Scholar 

  84. L. Gu, S. Hagiwara, Q. Fan, M. Tanimoto, M. Kobata, M. Yamashita, T. Nishitani, T. Gohda, Z. Ni, J. Qian, S. Horikoshi, Y. Tomino, Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes. Nephrol. Dial. Transplant. 21, 299–313 (2006)

    CAS  PubMed  Google Scholar 

  85. G. Gruden, G. Setti, A. Hayward, D. Sugden, S. Duggan, D. Burt, R.E. Buckingham, L. Gnudi, G. Viberti, 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)

    CAS  PubMed  Google Scholar 

  86. J. Cheng, M.M. Diaz Encarnacion, G.M. Warner, C.E. Gray, K.A. Nath, J.P. Grande, TGF-beta1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process. Am. J. Physiol. Cell Physiol. 289, C959–C970 (2005)

    CAS  PubMed  Google Scholar 

  87. W. Qi, X. Chen, T.S. Polhill, S. Sumual, S. Twigg, R.E. Gilbert, C.A. Pollock, TGF-β1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway. Am. J. Physiol. Renal Physiol. 290, F703–F709 (2006)

    CAS  PubMed  Google Scholar 

  88. B.H. Rovin, T. Yoshiumura, L. Tan, Cytokine-induced production of monocyte chemoattractant protein-1 by cultured human mesangial cells. J. Immunol. 148, 2148–2153 (1992)

    CAS  PubMed  Google Scholar 

  89. Y. Watanabe, M. Tamura, A. Osajima, H. Anai, N. Kabashima, R. Serino, Y. Nakashima, Integrins induce expression of monocyte chemoattractant protein-1 via focal adhesion kinase in mesangial cells. Kidney Int. 64, 431–440 (2003)

    CAS  PubMed  Google Scholar 

  90. A.A. Eddy, C.M. Giachelli, Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int. 47, 1546–1557 (1995)

    CAS  PubMed  Google Scholar 

  91. Y. Wang, J. Chen, L. Chen, Y.C. Tay, G.K. Rangan, D.C. Harris, Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J. Am. Soc. Nephrol. 8, 1537–1545 (1997)

    CAS  PubMed  Google Scholar 

  92. S. Giunti, Targeting the MCP-1/CCR2 system in diabetic kidney disease. Curr. Vasc. Pharmacol. 8, 849–860 (2010)

    CAS  PubMed  Google Scholar 

  93. S. Giunti, F. Barutta, P.C. Perin, G. Gruden, The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells. Kidney Int. 69, 856–863 (2006)

    CAS  PubMed  Google Scholar 

  94. D. Burt, G. Salvidio, E. Tarabra, F. Barutta, S. Pinach, P. Dentelli, G. Camussi, P.C. Perin, G. Gruden, The monocyte chemoattractant protein-1/cognate CC chemokine receptor 2 system affects cell motility in cultured human podocytes. Am. J. Pathol. 171, 1789–1799 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. V.H. Rao, D.T. Meehan, D. Delimont, M. Nakajima, T. Wada, M.A. Gratton, D. Cosgrove, Role for macrophage metalloelastase in glomerular basement membrane damage associated with alport syndrome. Am. J. Pathol. 169, 32–46 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  96. S. Giunti, G.H. Tesch, S. Pinach, D.J. Burt, M.E. Cooper, P. Cavallo-Perin, G. Camussi, G. Gruden, Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells. Diabetologia 51, 198–207 (2008)

    CAS  PubMed  Google Scholar 

  97. J. Park, D.R. Ryu, J.J. Li, D.S. Jung, S.J. Kwak, S.H. Lee, T.H. Yoo, S.H. Han, J.E. Lee, D.K. Kim, S.J. Moon, K. Kim, D.S. Han, S.W. Kang, MCP-1/CCR2 system is involved in high glucose-induced fibronectin and type IV collagen expression in cultured mesangial cells. Am. J. Physiol. Renal Physiol. 295, F749–F757 (2008)

    CAS  PubMed  Google Scholar 

  98. B.Y. Nam, J. Paeng, S.H. Kim, S.H. Lee, H. do Kim, H.Y. Kang, J.J. Li, S.J. Kwak, J.T. Park, T.H. Yoo, S.H. Han, D.K. Kim, S.W. Kang, The MCP-1/CCR2 axis in podocytes is involved in apoptosis induced by diabetic conditions. Apoptosis 17, 1–13 (2012)

    CAS  PubMed  Google Scholar 

  99. H. Kanamori, T. Matsubara, A. Mima, E. Sumi, K. Nagai, T. Takahashi, H. Abe, N. Iehara, A. Fukatsu, H. Okamoto, T. Kita, T. Doi, H. Arai, Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochem. Biophys. Res. Commun. 360, 772–777 (2007)

    CAS  PubMed  Google Scholar 

  100. P. Celec, J. Hodosy, R. Gardlík, M. Behuliak, R. Pálffy, M. Pribula, P. Jáni, J. Turňa, K. Sebeková, The effects of anti-Inflammatory and anti-angiogenic DNA vaccination on diabetic nephropathy in rats. Hum. Gene Ther. 23, 158–166 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  101. A.S. Awad, G.R. Kinsey, K. Khutsishvili, T. Gao, W.K. Bolton, M.D. Okusa, Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury. Am. J. Physiol. Renal Physiol. 301, F1358–F1366 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  102. S.J. Seok, E.S. Lee, G.T. Kim, M. Hyun, J.H. Lee, S. Chen, R. Choi, H.M. Kim, E.Y. Lee, C.H. Chung, Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol. Dial. Transplant. 28, 1700–1710 (2013)

    CAS  PubMed  Google Scholar 

  103. M. Okamoto, M. Fuchigami, T. Suzuki, N. Watanabe, A novel C-C chemokine receptor 2 antagonist prevents progression of albuminuria and atherosclerosis in mouse models. Biol. Pharm. Bull. 35, 2069–2074 (2012)

    CAS  PubMed  Google Scholar 

  104. S.G. Sayyed, M. Ryu, O.P. Kulkarni, H. Schmid, J. Lichtnekert, S. Grüner, L. Green, P. Mattei, G. Hartmann, H.J. Anders, An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 80, 68–78 (2011)

    CAS  PubMed  Google Scholar 

  105. T.J. Sullivan, Z. Miao, D.J. Dairaghi, A. Krasinski, Y. Wang, B.N. Zhao, T. Baumgart, L.S. Ertl, A. Pennell, L. Seitz, J. Powers, R. Zhao, S. Ungashe, Z. Wei, L. Boring, C.L. Tsou, I. Charo, R.D. Berahovich, T.J. Schall, J.C. Jaen, CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am. J. Physiol. Renal Physiol. 305, F1288–F1297 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  106. T.J. Sullivan, Z. Miao, B.N. Zhao, L.S. Ertl, Y. Wang, A. Krasinski, M.J. Walters, J.P. Powers, D.J. Dairaghi, T. Baumgart, L.C. Seitz, R.D. Berahovich, T.J. Schall, J.C. Jaen, Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes. Metab. Clin. Exp. 62, 1623–1632 (2013)

    CAS  PubMed  Google Scholar 

  107. J.F. Navarro-González, C. Mora-Fernández, M. de Muros Fuentes, J. García-Pérez, Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat. Rev. Nephrol. 7, 327–340 (2011)

    PubMed  Google Scholar 

  108. M. Hanefeld, E. Schell, I. Gouni-Berthold, M. Melichar, I. Vesela, D. Johnson, S. Miao, T.J. Sullivan, J.C. Jaen, T.J. Schall, P. Bekker, the CCX140-B Diabetes Study Group, Orally-administered chemokine receptor CCR2 antagonist CCX140-B in type 2 diabetes: a pilot double-blind, randomized clinical trial. J. Diabetes Metabolism. 3, 9 (2012)

    Google Scholar 

  109. V. Ninichuk, S. Clauss, O. Kulkarni, H. Schmid, S. Segerer, E. Radomska, D. Eulberg, K. Buchner, N. Selve, S. Klussmann, H.J. Anders, Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-3’PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice. Am. J. Pathol. 172, 628–637 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  110. S. Kiyici, E. Erturk, F. Budak, C. Ersoy, E. Tuncel, C. Duran, B. Oral, D. Sigirci, S. Imamoglu, Serum monocyte chemoattractant protein-1 and monocyte adhesion molecules in type 1 diabetic patients with nephropathy. Arch. Med. Res. 37, 998–1003 (2006)

    CAS  PubMed  Google Scholar 

  111. T. Wada, K. Furuichi, N. Sakai, Y. Iwata, K. Yoshimoto, M. Shimizu, S.I. Takeda, K. Takasawa, M. Yoshimura, H. Kida, K.I. Kobayashi, N. Mukaida, T. Naito, K. Matsushima, H. Yokoyama, Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 58, 1492–1499 (2000)

    CAS  PubMed  Google Scholar 

  112. N.G. Frangogiannis, The prognostic value of monocyte chemoattractant protein-1/CCL2 in acute coronary syndromes. J. Am. Coll. Cardiol. 50, 2125–2127 (2007)

    CAS  PubMed  Google Scholar 

  113. T. Morii, H. Fujita, T. Narita, T. Shimotomai, H. Fujishima, N. Yoshioka, H. Imai, M. Kakei, S. Ito, Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J. Diabetes Complicat. 17(1), 11–15 (2003)

    PubMed  Google Scholar 

  114. F.W. Tam, B.L. Riser, K. Meeran, J. Rambow, C.D. Pusey, A.H. Frankel, Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy. Cytokine 47, 37–42 (2009)

    CAS  PubMed  Google Scholar 

  115. M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, M. Watanabe, Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 9, 309–380 (2009)

    Google Scholar 

  116. J. Tam, J. Liu, B. Mukhopadhyay, R. Cinar, G. Godlewski, G. Kunos, Endocannabinoids in liver disease. Hepatology 53, 346–355 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  117. P. Pacher, P. Mukhopadhyay, R. Mohanraj, G. Godlewski, S. Bátkai, G. Kunos, Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension 52, 601–607 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  118. C. Silvestri, V. Di Marzo, The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 17, 475–490 (2013)

    CAS  PubMed  Google Scholar 

  119. N. Leleu-Chavain, M. Body-Malapel, J. Spencer, P. Chavatte, P. Desreumaux, R. Millet, Recent advances in the development of selective CB(2) agonists as promising anti-inflammatory agents. Curr. Med. Chem. 19, 3457–3474 (2012)

    CAS  PubMed  Google Scholar 

  120. F. Barutta, F. Piscitelli, S. Pinach, G. Bruno, R. Gambino, M.P. Rastaldi, G. Salvidio, V. Di Marzo, P. Cavallo Perin, G. Gruden, Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes 60, 2386–2396 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  121. F. Barutta, A. Corbelli, R. Mastrocola, R. Gambino, V. Di Marzo, S. Pinach, M.P. Rastaldi, P.C. Perin, G. Gruden, Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy. Diabetes 59, 1046–1054 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  122. K.H. Han, S. Lim, J. Ryu, C.W. Lee, Y. Kim, J.H. Kang, S.S. Kang, Y.K. Ahn, C.S. Park, J.J. Kim, CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc. Res. 84, 378–386 (2009)

    CAS  PubMed  Google Scholar 

  123. D.H. Nam, Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 153, 1387–1396 (2012)

    CAS  PubMed  Google Scholar 

  124. J.C. Lim, M.H. Lee, J.E. Kim, H.K. Song, Y.S. Kang, J.E. Lee, H.W. Kim, J.J. Cha, Y.Y. Hyun, S.H. Kim, S.Y. Han, K.H. Han, J.Y. Han, D.R. Cha, Cannabinoid receptor 1 mediates high glucose-induced apoptosis via endoplasmic reticulum stress in primary cultured rat mesangial cells. Am. J. Physiol. Renal Physiol. 301, F179–F188 (2011)

    CAS  PubMed  Google Scholar 

  125. F. Barutta, S. Grimaldi, I. Franco, S. Bellini, R. Gambino, S. Pinach, A. Corbelli, G. Bruno, M.P. Rastaldi, T. Aveta, E. Hirsch, V. Di Marzo, G. Gruden, Deficiency of cannabinoid receptor of type 2 worsens renal functional and structural abnormalities in streptozotocin-induced diabetic mice. Kidney Int. (2014). doi:10.1038/ki.2014.165

    PubMed  Google Scholar 

  126. K.A. Jenkin, A.J. McAinch, J.F. Briffa, Y. Zhang, D.J. Kelly, C.A. Pollock, P. Poronnik, D.H. Hryciw, Cannabinoid receptor 2 expression in human proximal tubule cells is regulated by albumin independent of ERK1/2 signaling. Cell. Physiol. Biochem. 32, 1309–1319 (2013)

    CAS  PubMed  Google Scholar 

  127. P. Janiak, B. Poirier, J.P. Bidouard, C. Cadrouvele, F. Pierre, L. Gouraud, I. Barbosa, J. Dedio, J.P. Maffrand, G. Le Fur, S. O’Connor, J.M. Herbert, Blockade of cannabinoid CB1 receptor improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int. 72, 1345–1357 (2007)

    CAS  PubMed  Google Scholar 

  128. F. Montecucco, F. Burger, F. Mach, S. Steffens, CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am. J. Physiol. Heart Circ. Physiol. 294, H1145–H1155 (2008)

    CAS  PubMed  Google Scholar 

  129. J. Tam, V.K. Vemuri, J. Liu, S. Bátkai, B. Mukhopadhyay, G. Godlewski, D. Osei-Hyiaman, S. Ohnuma, S.V. Ambudkar, J. Pickel, A. Makriyannis, G. Kunos, Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 120, 2953–2966 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  130. S. Steffens, N.R. Veillard, C. Arnaud, G. Pelli, F. Burger, C. Staub, M. Karsak, A. Zimmer, J.L. Frossard, F. Mach, Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434, 782–786 (2005)

    CAS  PubMed  Google Scholar 

  131. G.D. Duerr, J.C. Heinemann, G. Suchan, E. Kolobara, D. Wenzel, C. Geisen, M. Matthey, K. Passe-Tietjen, W. Mahmud, A. Ghanem, K. Tiemann, J. Alferink, S. Burgdorf, R. Buchalla, A. Zimmer, B. Lutz, A. Welz, B.K. Fleischmann, O. Dewald, The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy. Basic Res. Cardiol. 109, 425 (2014)

    PubMed  Google Scholar 

  132. E.J. Rahn, A.G. Hohmann, Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 6, 713–737 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  133. P. Pacher, R. Mechoulam, Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog. Lipid Res. 50, 193–211 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  134. V. Deveaux, T. Cadoudal, Y. Ichigotani, F. Teixeira-Clerc, A. Louver, S. Manin, J. Tran-Van Nhieu, M.P. Belot, A. Zimmer, P. Even, P.D. Cani, C. Knauf, R. Burcelin, A. Bertola, Y. Le Marchand-Brustel, P. Gual, A. Mallat, S. Lotersztajn, Cannabinoid CB2 receptor potentiates obesity-associated inflammation, Insulin resistance and hepatic steatosis. PloS One. 4(6), e5844 (2009)

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Acknowledgments

This work was supported by the European Federation for the Study of Diabetes, the Compagnia di San Paolo, and the University of Turin.

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Barutta, F., Bruno, G., Grimaldi, S. et al. Inflammation in diabetic nephropathy: moving toward clinical biomarkers and targets for treatment. Endocrine 48, 730–742 (2015). https://doi.org/10.1007/s12020-014-0437-1

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