Immune responses in diabetic nephropathy: Pathogenic mechanisms and therapeutic target

Abstract

Diabetic nephropathy (DN) is a chronic, inflammatory disease affecting millions of diabetic patients worldwide. DN is associated with proteinuria and progressive slowing of glomerular filtration, which often leads to end-stage kidney diseases. Due to the complexity of this metabolic disorder and lack of clarity about its pathogenesis, it is often more difficult to diagnose and treat than other kidney diseases. Recent studies have highlighted that the immune system can inadvertently contribute to DN pathogenesis. Cells involved in innate and adaptive immune responses can target the kidney due to increased expression of immune-related localization factors. Immune cells then activate a pro-inflammatory response involving the release of autocrine and paracrine factors, which further amplify inflammation and damage the kidney. Consequently, strategies to treat DN by targeting the immune responses are currently under study. In light of the steady rise in DN incidence, this timely review summarizes the latest findings about the role of the immune system in the pathogenesis of DN and discusses promising preclinical and clinical therapies.

Keywords: diabetic nephropathy; immune responses; inflammation; pathogenesis; therapeutic target.

Figure 1

Overview of the pathogenesis of DN. In the diabetic milieu, hyperglycemia, advanced glycation end-products (AGEs), angiotensin II, and oxidative stress activate a variety of signaling cascades driving the recruitment and activation of immune cells to promote the development of inflammation and ultimately leading to a series of pathological changes in DN. AGEs, advanced glycation end products; DAMPs, damage associated molecular patterns; PRRs, pattern recognition receptors; GBM, glomerular basement membrane.

Figure 2

Macrophage recruitment and activation in DN. Hyperglycemia induces increased expression of cell adhesion molecules (ICAM-1/VCAM-1) and chemokines (MCP-1/CSF-1), thereby enhancing the recruitment of monocytes to the kidney. Chemokines also promote transendothelial migration. Monocytes mature into macrophages and subsequently release inflammatory cytokines, leading to the progression of DN.

Figure 3

NF-κB signaling pathway in DN. NF-κB is a transcriptional regulator expressed in the cytoplasm of almost all cell types, and its activity is controlled by the IκB regulatory protein family. Activation of NF-κB involves the inhibitory protein IκB kinase being phosphorylated by specific IκB and subsequently degraded by proteolysis. Free NF-κB translocates to the nucleus, binds to promoter and enhancer sites, and activates transcription. NF-κB signaling pathway leads to increased transcription of target genes encoding inflammatory cytokines and other target genes associated with this complication, resulting in renal inflammation.

Figure 4

Activation and inhibition of JAK-STAT signaling pathways. Black arrows indicate the activation process and the red dotted arrows indicated inhibition process.