Empagliflozin Attenuates Renal Fibrosis in a Rodent Model of Fabry Disease by Modulating Inflammation and Myofibroblast Differentiation

Background: Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of glycosphingolipids and progressive organ damage, particularly in the kidneys. Although enzyme replacement therapy (ERT) is the standard treatment and can slow disease progression, it does not fully prevent ongoing renal injury. Emerging evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may provide additional renoprotective effects, including reductions in proteinuria and a slower decline in kidney function in chronic kidney disease. This study aimed to investigate the effects of empagliflozin on renal structure and function in a rodent model of Fabry disease. Methods: Wild-type and α-galactosidase A knockout mice were treated with empagliflozin or vehicle for 12 weeks. Renal fibrosis and inflammation were assessed using histological and molecular analyses. Results: Empagliflozin treatment in Fabry mice significantly reduced renal fibrosis, as demonstrated by trichrome and Sirius red staining, and attenuated myofibroblast differentiation, evidenced by decreased α-SMA expression. Additionally, empagliflozin downregulated renal mRNA expression of fibronectin, COL4A1, and TNF-α, while protein levels of key antioxidant enzymes (HO-1, SOD1, SOD2, NQO1, and catalase) remained unaffected. Despite no change in urinary albumin excretion, creatinine clearance was significantly improved in empagliflozin-treated Fabry mice. Conclusion: Empagliflozin attenuates renal interstitial fibrosis in Fabry disease, likely through the suppression of inflammation and myofibroblast activation. These findings support its potential as an adjunctive therapy in Fabry nephropathy. Funding: Private Foundation Support