Background: Chronic kidney disease (CKD) is the end stage of progressive renal disorders, and effective disease modifying treatments remain elusive. Diabetic kidney disease (DKD) is its leading cause, yet mechanisms and therapies still hold large knowledge gaps. Studies have demonstrated that tubules and interstitium constitute 90 % of renal parenchyma and drive DKD progression; high-glucose milieu induces renal tubular epithelial cell (RTEC) senescence, a process central to DKD onset and worsening.
Methods: Using PubMed as the primary data source, this review first screened literature on 'DKD pathogenesis', revealing that the pivotal role of 'complement activation-induced cellular senescence' remains insufficiently characterized. A second, focused search was then conducted on 'complement system activation', from which studies explicitly linking complement activation to cellular senescence were distilled. The final corpus is organized around three core dimensions: latest discoveries, current research status, and mechanism-guided therapeutic strategies.
Results: Cellular senescence, defined as the irreversible growth arrest of cells in response to damaging stimuli, involves various mechanisms such as DNA methylation, oxidative stress, DNA damage response (DDR), mitochondrial dysfunction, and the continuous production of senescence-associated secretory phenotype (SASP) factors. Complement activation induces cellular senescence through the aforementioned processes, thereby promoting and exacerbating both the onset and progression of DKD.
Conclusion: In the high-glucose milieu, complement activation drives massive C5a release, which accelerates DKD progression by inducing renal tubular cell senescence. C5a-receptor antagonists have already demonstrated potent renoprotective effects, positioning C5a as a central target for future DKD drug development.
Keywords: C5a; Complement system; RTEC; cellular senescence; diabetic kidney disease.