Role of the adaptive immune system in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end-stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro-inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon-γ and tumor necrosis factor-α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Keywords: Adaptive immune system; Diabetic kidney disease; Inflammation.

Figure 1

T‐cell migration paradigm. Memory T cells are divided into circulating and non‐circulating subsets. Central memory T (Tcm) cells migration is similar to that of the naïve T cells, and these cells predominantly reside in lymphoid tissues. Effector memory T (Tem) cells can pass through lymphoid and non‐lymphoid organs, and join the blood through lymphatic vessels. Tissue‐resident memory (Trm) cells are positioned within tissues and do not recirculate during steady‐state conditions. NLT, non‐lymphoid tissue; SLO, secondary lymphoid organs.

Figure 2

Insulin resistance and kidney damage initiated by collaboration of T cells and macrophages. CD8⁺ T cells act as the starter of adipose inflammation, which triggers the anti‐inflammatory macrophages type to the pro‐inflammatory type and the resultant production of cytokines. Insulin resistance occurs after this process and as a result, progressively leads to end‐organ damage, such as the kidney. IL, interleukin; IP‐10, interferon‐γ‐inducible protein 10; M1, classically activated macrophages; M2, alternatively activated macrophages; MCP‐1, monocyte chemoattractant protein 1; MCP‐3, monocyte chemoattractant protein 3; MIF, migration inhibitory factor; NF‐κB, nuclear factor‐κB; RANTES, Regulated upon Activation, Normal T cell Expressed and Secreted; TGF‐ β, transforming growth factor‐β; TNF‐α, tumor necrosis factor‐α; Treg, regulatory T cells.