Mineralocorticoid Receptor/Rac1-Driven Podocyte Injury in Fabry Disease: Finerenone and Spironolactone migitate the overactive signaling cascade

Podocyte injury is a key driver of Fabry nephropathy (FN), precipitating proteinuria and renal decline. Although mechanisms remain partially elucidated, dysregulated pathways involving mineralocorticoid receptor (MR) activation and Rac1-SGK1 signaling are implicated. This study investigates the role of MR/Rac1/SGK1 signaling and evaluates the nephroprotective potential of MR antagonists (finerenone, spironolactone) and Rac1 inhibition in FN.An in vitro FD model was established via stable shRNA-mediated knockdown of GLA in a human podocyte cell line. The model was confirmed by a significant reduction in both GLA mRNA (RT-qPCR) and α-galactosidaseA protein (Western blot). Experimental groups included wild-type (WT) and GLA-deficient podocytes, subsequently treated with finerenone, spironolactone, or the Rac1 inhibitor, NSC23766. CCK-8 assays determined non-cytotoxic concentrations as10 nM finerenone, 25 µM spironolactone, and 50 µM NSC23766. The mRNA levels of MR, aldosterone, cortisol, Rac1, SGK1, 11β-HSD1, NOX5, IL-6, RhoA, Cdc42 and Rac1 protein levels were analyzed before and after treatment with finerenone, spironolactone, or NSC23766.Compared to WT, Fabry podocytes exhibited significant upregulation in gene expression for MR, aldosterone, cortisol, 11β-HSD1, Rac1, SGK1, NOX5, Cdc42, and IL-6, alongside downregulated RhoA. Consistent with these findings, Rac1 protein levels were also elevated. Treatment with finerenone or spironolactone markedly reduced gene expression of Rac1, SGK1, NOX5, 11β-HSD1, IL-6, Cdc42, and MR, decreased Rac1 protein, and increased RhoA transcription. Pharmacological Rac1 inhibition recapitulated these effects.Hyperactive MR-Rac1-SGK1 signaling might be a pivotal driver of podocyte injury in FN. Both MR antagonists and Rac1 inhibition normalize the dysregulation and restore RhoA, suggesting cytoskeletal stabilization. Finerenone, spironolactone, and Rac1 inhibition represent promising adjunct therapies in FN.