Role of the Immune System in Diabetic Kidney Disease
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).
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.
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.
KeywordsDiabetic kidney disease Inflammation Macrophages Leukocytes Cytokines
Compliance with Ethical Standards
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 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. PubMedGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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.Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedPubMedCentralGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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. Google Scholar
- 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.Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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. CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar