Complement anaphylatoxins: Potential therapeutic target for diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is the most common cause of kidney failure, characterized by chronic inflammation and fibrosis. The complement system is increasingly implicated in the development and progression of diabetic nephropathy. The important complement anaphylatoxins C3a and C5a are key mediators of the innate immune system, which regulates cellular inflammation, oxidative stress, mitochondrial homeostasis and tissue fibrosis. This review summarizes the involvement of anaphylatoxins in the pathogenesis of diabetic kidney disease, highlights their important roles in the pathophysiologic changes of glomerulopathy, tubulointerstitial damage and immune cell infiltration, and discusses the modulatory effects of new anti-diabetic drugs acting on the complement system. Based on available clinical data and findings from the preclinical studies of complement blockade, anaphylatoxin-targeted therapeutics may become a promising approach for patients with DKD in the future.

Keywords: anaphylatoxins; complement; diabetic kidney disease.

FIGURE 1

The complement cascade and anaphylatoxin formation. The complement cascade consists of a series of enzymatic reactions that respond to infection and danger signal in the immune system. The complement cascade is activated through three different pathways, namely classical, lectin and alternative pathways. These pathways converge at the cleavage of C3 to produce C3a (anaphylatoxin) and C3b. Excess C3b binds with C4b2a (C3 convertase) to form C4b2aC3b (C5 convertase), which cleavages C5 into C5a (anaphylatoxin) and C5b. Finally, C5b mediates the formation of membrane attack complex (MAC) that forms pores on the cellular membrane, resulting in cell death. This figure was created using BioRender.

FIGURE 2

The role of anaphylatoxins in DKD. Hyperglycaemia activates the complement system in patients with diabetes that generates anaphylatoxins C3a and C5a, which bind to the corresponding receptors (C3aR, C5aR1 and C5aR2) on various kidney resident cells (podocytes, glomerular endothelial cells and tubular epithelial cells) and recruited immune cells that orchestrate cellular responses to diabetes‐induced damage including inflammation, oxidative stress, mitochondrial dysfunction, epithelial–mesenchymal transition (EMT) and endothelial–myofibroblast transition (EndMT). Prolonged kidney injury and maladaptive repair result in DKD with kidney fibrosis and progressive loss of kidney function. This figure was created using BioRender.