Role of the Immune System in Diabetic Kidney Disease

Abstract

Purpose of Review

The purpose of this review is to examine the proposed role of immune modulation in the development and progression of diabetic kidney disease (DKD).

Recent Findings

Diabetic kidney disease has not historically been considered an immune-mediated disease; however, increasing evidence is emerging in support of an immune role in its pathophysiology. Both systemic and local renal inflammation have been associated with DKD. Infiltration of immune cells, predominantly macrophages, into the kidney has been reported in a number of both experimental and clinical studies. In addition, increased levels of circulating pro-inflammatory cytokines have been linked to disease progression. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease.

Summary

Although no current therapies for DKD are directly based on immune modulation many of the therapies in clinical use have anti-inflammatory effects along with their primary actions. Macrophages emerge as the most likely beneficial immune cell target and compounds which reduce macrophage infiltration to the kidney have shown potential in both animal models and clinical trials.

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

Fig. 1
Fig. 2

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, et al. United States renal data system 2011 annual data report: atlas of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis. 2012;59(1 Suppl 1):A7. e1-420

    Article  PubMed  Google Scholar 

  2. 2.

    Perlman AS, Chevalier JM, Wilkinson P, Liu H, Parker T, Levine DM, et al. Serum inflammatory and immune mediators are elevated in early stage diabetic nephropathy. Ann Clin Lab Sci. 2015;45(3):256–63.

    CAS  PubMed  Google Scholar 

  3. 3.

    Nguyen D, Ping F, Mu W, Hill P, Atkins RC, Chadban SJ. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton). 2006;11(3):226–31.

    Article  Google Scholar 

  4. 4.

    •• Klessens CQF, Zandbergen M, Wolterbeek R, Bruijn JA, Rabelink TJ, Bajema IM, et al. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2017;32(8):1322–9. This study investigated the presence and phenotype of glomerular and interstitial macrophages.

    PubMed  Google Scholar 

  5. 5.

    Sassy-Prigent C, Heudes D, Mandet C, Bélair MF, Michel O, Perdereau B, et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 2000;49(3):466–75.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Tesch GH. Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol. 2005;16(6):1711–22.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Chow FY, Nikolic-Paterson DJ, Ma FY, Ozols E, Rollins BJ, Tesch GH. 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. 2007;50(2):471–80.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Webster L, Abordo EA, Thornalley PJ, Limb GA. Induction of TNF alpha and IL-1 beta mRNA in monocytes by methylglyoxal- and advanced glycated endproduct-modified human serum albumin. Biochem Soc Trans. 1997;25(2):250S.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, et al. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003;108(9):1070–7.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Tesch GH. Role of macrophages in complications of type 2 diabetes. Clin Exp Pharmacol Physiol. 2007;34(10):1016–9.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    You H, Gao T, Cooper TK, Brian Reeves W, Awad AS. Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol. 2013;305(12):F1719–27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Rollin BJ, Tesch GH. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 2006;69(1):73–80.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Sayyed SG, Ryu M, Kulkarni OP, Schmid H, Lichtnekert J, Grüner S, et al. An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int. 2011;80(1):68–78.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Seok SJ, Lee ES, Kim GT, Hyun M, Lee JH, Chen S, et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol Dial Transplant. 2013;28(7):1700–10.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Sullivan T, Miao Z, Dairaghi DJ, Krasinski A, Wang Y, Zhao BN, et al. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol. 2013;305(9):F1288–97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    • de Zeeuw D, Bekker P, Henkel E, Hasslacher C, Gouni-Berthold I, Mehling H, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 2015;3(9):687–96. This clinical trial indicated that inhibition of CCR2 has renoprotective effects in patients with type 2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Kennedy A, Fearon U, Veale DJ, Godson C. Macrophages in synovial inflammation. Front Immunol. 2011;2:52.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int. 2004;65(1):116–28.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, et al. Macrophage cyclooxygenase-2 protects against development of diabetic nephropathy. Diabetes. 2017;66(2):494–504.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Zheng D, Wang Y, Cao Q, Lee VW, Zheng G, Sun Y, et al. Transfused macrophages ameliorate pancreatic and renal injury in murine diabetes mellitus. Nephron Exp Nephrol. 2011;118(4):e87–99.

    Article  PubMed  Google Scholar 

  22. 22.

    •• Sun H, Tian J, Xian W, Xie T, Yang X. Pentraxin-3 attenuates renal damage in diabetic nephropathy by promoting M2 macrophage differentiation. Inflammation. 2015;38(5):1739–47. This study in a mouse model of hyperglycaemia-induced nephropathy nicely demonstrated that pentraxin-3attenuated renal damage by promoting M2 macrophage differentiation.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Decker Y, McBean G, Godson C. Lipoxin A4 inhibits IL-1beta-induced IL-8 and ICAM-1 expression in 1321N1 human astrocytoma cells. Am J Physiol Cell Physiol. 2009;296(6):C1420–7.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Baker N, O’Meara SJ, Scannell M, Maderna P, Godson C. Lipoxin A4: anti-inflammatory and anti-angiogenic impact on endothelial cells. J Immunol. 2009;182(6):3819–26.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Börgeson E, Godson C. Molecular circuits of resolution in renal disease. S ScientificWorldJournal. 2010;10:1370–85.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Börgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O’Sullivan TP, et al. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J. 2011;25(9):2967–79.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Moon JY, Jeong KH, Lee TW, Ihm CG, Lim SJ, Lee SH. Aberrant recruitment and activation of T cells in diabetic nephropathy. Am J Nephrol. 2012;35(2):164–74.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Lim AK, Ma FY, Nikolic-Paterson DJ, Kitching AR, Thomas MC, Tesch GH. Lymphocytes promote albuminuria, but not renal dysfunction or histological damage in a mouse model of diabetic renal injury. Diabetologia. 2010;53(8):1772–82.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Herrera M, Söderberg M, Sabirsh A, Valastro B, Mölne J, Santamaria B, et al. Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease. Am J Physiol Renal Physiol. 2017;312(4):F748–F59.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Norlin J, Nielsen Fink L, Helding Kvist P, Douglas Galsgaard E, Coppieters K. Abatacept treatment does not preserve renal function in the streptozocin-induced model of diabetic nephropathy. PLoS One. 2016;11(4):e0152315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes. 2011;60(11):2954–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wu CC, Sytwu HK, Lu KC, Lin YF. Role of T cells in type 2 diabetic nephropathy. Exp Diabetes Res. 2011;2011:514738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    • Zhang C, Xiao C, Wang P, Xu W, Zhang A, Li Q, et al. The alteration of Th1/Th2/Th17/Treg paradigm in patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Hum Immunol. 2014;75(4):289–96. This study demonstrated that alterations in the proportions of Th1/Th2/Th17/Treg cells are skewed towards Th1 and Th17 in patients with type 2 diabetes.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Kim SM, Lee SH, Lee A, Kim DJ, Kim YG, Kim SY, et al. Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. Transl Res. 2015;166(4):375–83.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Mohamed R, Jayakumar C, Chen F, Fulton D, Stepp D, Gansevoort RT, et al. Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. J Am Soc Nephrol. 2016;27(3):745–65.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Kuo HL, Huang CC, Lin TY, Lin CY. IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy. Nephrol Dial Transplant. 2018;33:248–256.

  37. 37.

    Xiao X, Ma B, Dong B, Zhao P, Tai N, Chen L, et al. Cellular and humoral immune responses in the early stages of diabetic nephropathy in NOD mice. J Autoimmun. 2009;32(2):85–93.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Lopes-Virella MF, Carter RE, Baker NL, Lachin J, Virella G, Group DER. High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in type 1 diabetes. Nephrol Dial Transplant. 2012;27(4):1416–23.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Lopes-Virella MF, Hunt KJ, Baker NL, Virella G, Investigators VGo. High levels of AGE-LDL, and of IgG antibodies reacting with MDA-lysine epitopes expressed by oxLDL and MDA-LDL in circulating immune complexes predict macroalbuminuria in patients with type 2 diabetes. J Diabetes Complicat. 2016;30(4):693–9.

    Article  PubMed  Google Scholar 

  40. 40.

    Okoń K, Stachura J. Increased mast cell density in renal interstitium is correlated with relative interstitial volume, serum creatinine and urea especially in diabetic nephropathy but also in primary glomerulonephritis. Pol J Pathol. 2007;58(3):193–7.

    PubMed  Google Scholar 

  41. 41.

    Zheng JM, Yao GH, Cheng Z, Wang R, Liu ZH. Pathogenic role of mast cells in the development of diabetic nephropathy: a study of patients at different stages of the disease. Diabetologia. 2012;55(3):801–11.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Jones SE, Gilbert RE, Kelly DJ. Tranilast reduces mesenteric vascular collagen deposition and chymase-positive mast cells in experimental diabetes. J Diabetes Complicat. 2004;18(5):309–15.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Wu CC, Chen JS, Lu KC, Chen CC, Lin SH, Chu P, et al. Aberrant cytokines/chemokines production correlate with proteinuria in patients with overt diabetic nephropathy. Clin Chim Acta. 2010;411(9–10):700–4.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Mensah-Brown EP, Obineche EN, Galadari S, Chandranath E, Shahin A, Ahmed I, et al. Streptozotocin-induced diabetic nephropathy in rats: the role of inflammatory cytokines. Cytokine. 2005;31(3):180–90.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, 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(5):605–8.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    • Chen YL, Qiao YC, Xu Y, Ling W, Pan YH, Huang YC, et al. Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: a systematic review and meta-analysis. Immunol Lett. 2017;186:52–8. A systematic review of serum TNF-α in patients with type 2 diabetes with or without associated DKD.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Navarro JF, Mora C, Muros M, García J. Urinary tumour necrosis factor-alpha excretion independently correlates with clinical markers of glomerular and tubulointerstitial injury in type 2 diabetic patients. Nephrol Dial Transplant. 2006;21(12):3428–34.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Koike N, Takamura T, Kaneko S. Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-alpha stimulation, and effects of a phosphodiesterase inhibitor. Life Sci. 2007;80(18):1721–8.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol. 1988;141(8):2629–34.

    CAS  PubMed  Google Scholar 

  50. 50.

    Moriwaki Y, Inokuchi T, Yamamoto A, Ka T, Tsutsumi Z, Takahashi S, et al. Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 2007;44(4):215–8.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    •• Awad AS, You H, Gao T, Cooper TK, Nedospasov SA, Vacher J, et al. Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury. Kidney Int. 2015;88(4):722–33. This study demonstrated kidney protection in a mouse model of DKD by blockade of macrophage-derived TNF-α.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Carr MW, Roth SJ, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994;91(9):3652–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Xu LL, Warren MK, Rose WL, Gong W, Wang JM. Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro. J Leukoc Biol. 1996;60(3):365–71.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    • Shoukry A, Bdeer S-A, El-Sokkary RH. Urinary monocyte chemoattractant protein-1 and vitamin D-binding protein as biomarkers for early detection of diabetic nephropathy in type 2 diabetes mellitus. Mol Cell Biochem. 2015;408(1–2):25–35. This study identified urinary MCP-1 as a potential novel biomarker for early detection of DKD.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Titan SM, Vieira JM, Dominguez WV, Moreira SR, Pereira AB, Barros RT, et al. Urinary MCP-1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy. J Diabetes Complicat. 2012;26(6):546–53.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Kanamori H, Matsubara T, Mima A, Sumi E, Nagai K, Takahashi T, et al. Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy. Biochem Biophys Res Commun. 2007;360(4):772–7.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Li C, Yang CW, Park CW, Ahn HJ, Kim WY, Yoon KH, et al. Long-term treatment with ramipril attenuates renal osteopontin expression in diabetic rats. Kidney Int. 2003;63(2):454–63.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Mizuno M, Sada T, Kato M, Fukushima Y, Terashima H, Koike H. The effect of angiotensin II receptor blockade on an end-stage renal failure model of type 2 diabetes. J Cardiovasc Pharmacol. 2006;48(4):135–42.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Amann B, Tinzmann R, Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care. 2003;26(8):2421–5.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, et al. Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol. 2006;17(5):1362–72.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Utimura R, Fujihara CK, Mattar AL, Malheiros DM, Noronha IL, Zatz R, et al. Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney Int. 2003;63(1):209–16.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Wu YG, Lin H, Qian H, Zhao M, Qi XM, Wu GZ, et al. Renoprotective effects of combination of angiotensin converting enzyme inhibitor with mycophenolate mofetil in diabetic rats. Inflamm Res. 2006;55(5):192–9.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Hickey FB, Martin F. Diabetic kidney disease and immune modulation. Curr Opin Pharmacol. 2013;13(4):602–12.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Ninichuk V, Clauss S, Kulkarni O, Schmid H, Segerer S, Radomska E, et al. 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. 2008;172(3):628–37.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    •• Boels MGS, Koudijs A, Avramut MC, Sol WMPJ, Wang G, van Oeveren-Rietdijk AM, et al. Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy. Am J Pathol. 2017:2430–40 This study nicely demonstrated the therapeutic potential of MCP-1 inhibition in a mouse model of DKD.

  66. 66.

    Senthilkumar GP, Anithalekshmi MS, Yasir M, Parameswaran S, Packirisamy RM, Bobby Z. Role of omentin 1 and IL-6 in type 2 diabetes mellitus patients with diabetic nephropathy. Diabetes Metab Syndr. 2018;12:23–26.

  67. 67.

    Choudhary N, Ahlawat RS. Interleukin-6 and C-reactive protein in pathogenesis of diabetic nephropathy: new evidence linking inflammation, glycemic control, and microalbuminuria. Iran J Kidney Dis. 2008;2(2):72–9.

    PubMed  Google Scholar 

  68. 68.

    Ng DP, Nurbaya S, Ye SH, Krolewski AS. An IL-6 haplotype on human chromosome 7p21 confers risk for impaired renal function in type 2 diabetic patients. Kidney Int. 2008;74(4):521–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Papaoikonomou S, Tentolouris N, Tousoulis D, Papadodiannis D, Miliou A, Papageorgiou N, et al. The association of the 174G>C polymorphism of interleukin 6 gene with diabetic nephropathy in patients with type 2 diabetes mellitus. J Diabetes Complicat. 2013;27(6):576–9.

    Article  PubMed  Google Scholar 

  70. 70.

    Chang WT, Huang MC, Chung HF, Chiu YF, Chen PS, Chen FP, et al. Interleukin-6 gene polymorphisms correlate with the progression of nephropathy in Chinese patients with type 2 diabetes: a prospective cohort study. Diabetes Res Clin Pract. 2016;120:15–23.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Watanabe T, Tomioka NH, Doshi M, Watanabe S, Tsuchiya M, Hosoyamada M. Macrophage migration inhibitory factor is a possible candidate for the induction of microalbuminuria in diabetic db/db mice. Biol Pharm Bull. 2013;36(5):741–7.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Herder C, Kolb H, Koenig W, Haastert B, Müller-Scholze S, Rathmann W, et al. Association of systemic concentrations of macrophage migration inhibitory factor with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg, Survey 4 (KORA S4). Diabetes Care. 2006;29(2):368–71.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Sanchez-Niño MD, Sanz AB, Ihalmo P, Lassila M, Holthofer H, Mezzano S, et al. The MIF receptor CD74 in diabetic podocyte injury. J Am Soc Nephrol. 2009;20(2):353–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    • Wang Z, Wei M, Wang M, Chen L, Liu H, Ren Y, et al. Inhibition of macrophage migration inhibitory factor reduces diabetic nephropathy in type II diabetes mice. Inflammation. 2014;37(6):2020–9. This study highlights MIF inhibition as a potential therapeutic strategy in DKD.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Tang LQ, Ni WJ, Cai M, Ding HH, Liu S, Zhang ST. Renoprotective effects of berberine and its potential effect on the expression of β-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats. J Diabetes. 2016;8(5):693–700.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Clausen P, Jacobsen P, Rossing K, Jensen JS, Parving HH, Feldt-Rasmussen B. Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with type 1 diabetes mellitus with microalbuminuria and overt nephropathy. Diabet Med. 2000;17(9):644–9.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Güler S, Cakir B, Demirbas B, Yönem A, Odabasi E, Onde U, et al. Plasma soluble intercellular adhesion molecule 1 levels are increased in type 2 diabetic patients with nephropathy. Horm Res. 2002;58(2):67–70.

    PubMed  Google Scholar 

  78. 78.

    Wong CK, Ho AW, Tong PC, Yeung CY, Chan JC, Kong AP, et al. Aberrant expression of soluble co-stimulatory molecules and adhesion molecules in type 2 diabetic patients with nephropathy. J Clin Immunol. 2008;28(1):36–43.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Rubio-Guerra AF, Vargas-Robles H, Lozano Nuevo JJ, Escalante-Acosta BA. Correlation between circulating adhesion molecule levels and albuminuria in type-2 diabetic hypertensive patients. Kidney Blood Press Res. 2009;32(2):106–9.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Polat SB, Ugurlu N, Aslan N, Cuhaci N, Ersoy R, Cakir B. Evaluation of biochemical and clinical markers of endothelial dysfunction and their correlation with urinary albumin excretion in patients with type 1 diabetes mellitus. Arch Endocrinol Metab. 2016;60(2):117–24.

    Article  PubMed  Google Scholar 

  81. 81.

    Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes. 2003;52(10):2586–93.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Anderson ME, Siahaan TJ. Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: designing peptide and small molecule inhibitors. Peptides. 2003;24(3):487–501.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    •• Shahzad K, Bock F, Dong W, Wang H, Kopf S, Kohli S, et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015;87(1):74–84. This study demonstrates renal inflammasome activation in an experimental DKD model and also in clinical samples and shows that IL-1R blockade prevents DKD.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol. 2016;12(1):13–26.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Wang C, Pan Y, Zhang QY, Wang FM, Kong LD. Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS One. 2012;7(6):e38285.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Gao P, Meng XF, Su H, He FF, Chen S, Tang H, et al. Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy. Biochim Biophys Acta. 2014;1843(11):2448–60.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Anders HJ. Of inflammasomes and alarmins: IL-1β and IL-1α in kidney disease. J Am Soc Nephrol. 2016;27(9):2564–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Soetikno V, Sari FR, Veeraveedu PT, Thandavarayan RA, Harima M, Sukumaran V, et al. Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. Nutr Metab (Lond). 2011;8(1):35.

    CAS  Article  Google Scholar 

  89. 89.

    Sakai N, Wada T, Furuichi K, Iwata Y, Yoshimoto K, Kitagawa K, et al. p38 MAPK phosphorylation and NF-kappa B activation in human crescentic glomerulonephritis. Nephrol Dial Transplant. 2002;17(6):998–1004.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner B, Eichinger F, et al. Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes. 2006;55(11):2993–3003.

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Yi B, Hu X, Zhang H, Huang J, Liu J, Hu J, et al. Nuclear NF-κB p65 in peripheral blood mononuclear cells correlates with urinary MCP-1, RANTES and the severity of type 2 diabetic nephropathy. PLoS One. 2014;9(6):e99633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Deb DK, Chen Y, Zhang Z, Zhang Y, Szeto FL, Wong KE, et al. 1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway. Am J Physiol Renal Physiol. 2009;296(5):F1212–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Spandou E, Tsouchnikas I, Karkavelas G, Dounousi E, Simeonidou C, Guiba-Tziampiri O, et al. Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant. 2006;21(2):330–6.

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Tan X, Wen X, Liu Y. Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol. 2008;19(9):1741–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Kuhad A, Chopra K. Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci. 2009;84(9–10):296–301.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Ahn KS, Sethi G, Krishnan K, Aggarwal BB. Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem. 2007;282(1):809–20.

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Lee FT, Cao Z, Long DM, Panagiotopoulos S, Jerums G, Cooper ME, et al. Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy. J Am Soc Nephrol. 2004;15(8):2139–51.

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Kolati SR, Kasala ER, Bodduluru LN, Mahareddy JR, Uppulapu SK, Gogoi R, et al. BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-κB pathway. Environ Toxicol Pharmacol. 2015;39(2):690–9.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Najafian B, Alpers CE, Fogo AB. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36–47.

    Article  PubMed  Google Scholar 

  100. 100.

    Mise K, Hoshino J, Ueno T, Sumida K, Hiramatsu R, Hasegawa E, et al. Clinical implications of linear immunofluorescent staining for immunoglobulin G in patients with diabetic nephropathy. Diabetes Res Clin Pract. 2014;106(3):522–30.

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Mironova M, Virella G, Lopes-Virella MF. Isolation and characterization of human antioxidized LDL autoantibodies. Arterioscler Thromb Vasc Biol. 1996;16(2):222–9.

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Lopes-Virella MF, Virella G. The role of immune and inflammatory processes in the development of macrovascular disease in diabetes. Front Biosci. 2003;8:s750–68.

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Atchley DH, Lopes-Virella MF, Zheng D, Kenny D, Virella G. Oxidized LDL-anti-oxidized LDL immune complexes and diabetic nephropathy. Diabetologia. 2002;45(11):1562–71.

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Virella G, Carter RE, Saad A, Crosswell EG, Game BA, Lopes-Virella MF, et al. Distribution of IgM and IgG antibodies to oxidized LDL in immune complexes isolated from patients with type 1 diabetes and its relationship with nephropathy. Clin Immunol. 2008;127(3):394–400.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Hora K, Satriano JA, Santiago A, Mori T, Stanley ER, Shan Z, et al. Receptors for IgG complexes activate synthesis of monocyte chemoattractant peptide 1 and colony-stimulating factor 1. Proc Natl Acad Sci U S A. 1992;89(5):1745–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Abdelsamie SA, Li Y, Huang Y, Lee MH, Klein RL, Virella G, et al. Oxidized LDL immune complexes stimulate collagen IV production in mesangial cells via Fc gamma receptors I and III. Clin Immunol. 2011;139(3):258–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Saad AF, Virella G, Chassereau C, Boackle RJ, Lopes-Virella MF. OxLDL immune complexes activate complement and induce cytokine production by MonoMac 6 cells and human macrophages. J Lipid Res. 2006;47(9):1975–83.

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Lopez-Parra V, Mallavia B, Lopez-Franco O, Ortiz-Muñoz G, Oguiza A, Recio C, et al. Fcγ receptor deficiency attenuates diabetic nephropathy. J Am Soc Nephrol. 2012;23(9):1518–27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Østergaard J, Hansen TK, Thiel S, Flyvbjerg A. Complement activation and diabetic vascular complications. Clin Chim Acta. 2005;361(1–2):10–9.

    Article  CAS  PubMed  Google Scholar 

  110. 110.

    Watanabe S, Tomino Y, Inoue W, Yagame M, Kaneshige H, Nomoto Y, et al. Detection of immunoglobulins and/or complement in kidney tissues from non-obese diabetic (NOD) mice. Tokai J Exp Clin Med. 1987;12(3):201–8.

    CAS  PubMed  Google Scholar 

  111. 111.

    Flyvbjerg A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol. 2017;13(5):311–8.

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Kelly KJ, Liu Y, Zhang J, Dominguez JH. Renal C3 complement component: feed forward to diabetic kidney disease. Am J Nephrol. 2015;41(1):48–56.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Woroniecka KI, Park AS, Mohtat D, Thomas DB, Pullman JM, Susztak K. Transcriptome analysis of human diabetic kidney disease. Diabetes. 2011;60(9):2354–69.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Fujita T, Ohi H, Komatsu K, Endo M, Ohsawa I, Kanmatsuse K. Complement activation accelerates glomerular injury in diabetic rats. Nephron. 1999;81(2):208–14.

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Li L, Yin Q, Tang X, Bai L, Zhang J, Gou S, et al. C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway. PLoS One. 2014;9(11):e113639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Finian Martin.

Ethics declarations

Conflict of Interest

Fionnuala Hickey and Finian Martin declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Microvascular Complications—Nephropathy

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hickey, F.B., Martin, F. Role of the Immune System in Diabetic Kidney Disease. Curr Diab Rep 18, 20 (2018). https://doi.org/10.1007/s11892-018-0984-6

Download citation

Keywords

  • Diabetic kidney disease
  • Inflammation
  • Macrophages
  • Leukocytes
  • Cytokines