The Role of Complement Component C5a in the Pathogenesis of Diabetic Kidney Disease: A New Kid on the Block?

Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus pandemic and raises awareness as it is considered a worldwide health burden with significant cardiovascular and all-cause morbidity and mortality leading to enormous social and economic consequences. The complex pathogenesis of DKD is multifactorial, involving hemodynamic, metabolic, inflammatory, and fibrotic pathways leading to progressive kidney damage. The significant overlap and dynamic nature of these interconnected pathways, alongside the activation of oxidative processes in different renal compartments, namely the glomeruli, vasculature, and tubulointerstitial space, have not yet been fully demystified; hence, DKD is a heterogeneous disease entity regarding its clinical manifestations, histopathology, and the rate of progression, making it difficult to develop effective therapies. However, recent research brings into focus the central role of complement activation in the development and progression of DKD. Complement cascade activation leads to the formation of anaphylatoxin C5a, a potent inflammatory mediator, which serves as a powerful attractant for neutrophils, monocytes and macrophages, increases vascular permeability, promotes mast cell degranulation and tissue regeneration and modulates effectively innate and adaptive immune responses. Growing evidence supports the pivotal role of elevated C5a levels as well as their activated receptors in DKD progression through activation of inflammatory pathways, mitochondrial dysfunction and generation of harmful reactive oxygen species, as well as premature aging of renal tubular epithelial cells that exacerbates the vicious cycle of inflammation and fibrosis. C5a/C5a receptors (C5aR) axis is assumed to be up-regulated early in the course of the disease and, interestingly, prior to overt clinical manifestations, contributing substantially to the progression of kidney inflammation, fibrosis and glomerulosclerosis, suggesting that it may be an early indicator of subclinical renal damage. Of note, tubular deposition of C5a has been correlated with the severity of renal damage and tubulointerstitial fibrosis in human biopsies, while elevated C5a levels in urine have been strongly associated with 10-year kidney failure risk. Also, increased C5a levels in urine have been identified as a valuable and accurate biomarker to stratify diabetic patients with DKD into rapid and slow progressors, implying that urine C5a levels are a reliable predictor of progression to end-stage kidney disease (ESKD). In experimental studies, therapeutic inhibition of C5a-activated signaling pathways seems to mitigate the above detrimental processes. More specifically, genetic deletion or pharmacological inhibition of the C5a/C5aR axis ameliorates kidney injury, albuminuria, and fibrosis through restoration of mitochondrial function, decrease of reactive oxygen species and inflammatory pathways, and attenuation of tubular epithelial cells premature aging. Hence, C5a/C5aR axis inhibition has emerged as a promising therapeutic target given that current therapy cannot completely prevent DKD progression to ESKD in many patients. Therefore, in this narrative review, we aim to summarize the available data from clinical and preclinical studies that unravel the central role of anaphylatoxin C5a in DKD pathophysiology and turn the spotlight of drug discovery efforts on complement-targeted therapeutics.