Alpha-actinin-3 deficiency links genetic susceptibility to renal fibrosis: evidence from hemodialysis patients and murine models

The X allele of ACTN3 R577X polymorphism results in α-actinin-3 deficiency and has been associated with muscle damage and impaired recovery. While its role has been explored in musculoskeletal and cardiac contexts, no studies have evaluated its impact on chronic kidney disease (CKD). To investigate the prevalence of the ACTN3 R577X polymorphism in patients with end-stage renal disease undergoing hemodialysis (HD) and explore its potential involvement in renal fibrosis through experimental models. A total of 217 HD patients and 413 healthy controls were genotyped for the ACTN3 R577X polymorphism. Associations with clinical variables were analyzed using multivariate regression. Renal Actn3 expression was evaluated in mice subjected to folic acid-induced acute and chronic kidney injury. In vitro, fibroblasts were exposed to TGF-β or LPS to assess gene expression responses. The X allele was significantly more frequent in HD patients (83.7% vs. 64.4%, p < 0.0001), and XX individuals began HD up to 11 years earlier than RR homozygotes. Experimental models showed persistent upregulation of Actn3 in fibrotic kidneys and in TGF-β-treated fibroblasts, but not in inflammatory conditions. Actn3 expression paralleled that of fibrosis markers such as Col1a1 and Acta2. The ACTN3 X allele is associated with earlier onset of renal failure and increased susceptibility to tubulointerstitial disease. Experimental data support its involvement in renal fibrosis. ACTN3 genotyping may help identify patients at greater risk for CKD progression.