Dotinurad, a novel urate reabsorption inhibitor, prolongs survival in Alport mice.

Abstract

Background: Hyperuricemia contributes to inflammatory conditions such as gout and is associated with liver dysfunction, cardiovascular disease, and immune cell activation. While the benefits of uric acid-lowering therapy in patients with chronic kidney disease (CKD) remain uncertain, dotinurad, a selective urate transporter 1 (URAT1) inhibitor, may provide renal benefits by reducing excessive uric acid reabsorption. This study investigates the effects of dotinurad on kidney function in a mouse model of Alport syndrome, a genetic model of CKD.

Methods: A mouse model of Alport syndrome was used to evaluate the effects of dotinurad on kidney function. Mice were treated with dotinurad, and their lifespan, urinary albumin-to-creatinine ratios, serum creatinine levels, urinary uric acid-to-creatinine ratios, and serum uric acid levels were assessed. Histological analysis was performed to evaluate glomerulosclerosis and tubulointerstitial fibrosis. Additionally, RNA sequencing was conducted to identify gene expression changes, with real-time reverse transcription polymerase chain reaction (RT-PCR) used to validate key findings.

Results: Dotinurad-treated mice exhibited a significantly longer lifespan than control mice. They also showed lower urinary albumin-to-creatinine ratios and serum creatinine levels, while urinary uric acid-to-creatinine ratios and serum uric acid levels remained unchanged. Histological analysis demonstrated reduced glomerulosclerosis and tubulointerstitial fibrosis in dotinurad-treated mice. RNA sequencing revealed a downregulation of inflammatory cytokines, which was further validated by RT-PCR.

Conclusions: These findings suggest that dotinurad may exert renoprotective effects in CKD. Further research is needed to confirm these effects in clinical settings.