Remogliflozin Attenuates Thioacetamide-Induced Nephrotoxicity: Association with Nrf2/HO-1, SIRT1/AMPK, and TLR4/NF-κB...

Thioacetamide (TAA) induces renal injury via oxidative stress and inflammation. Remogliflozin (Remo), an SGLT2 inhibitor, was evaluated for potential renoprotection. Twenty-four male Wistar rats were assigned to control, TAA (100 mg/kg IP twice weekly), TAA + Remo 25 mg/kg, or TAA + Remo 50 mg/kg (oral daily). Outcomes included renal function, oxidative stress (GSH, SOD, MDA), antioxidant biomarkers (Nrf2, HO-1), inflammatory mediators (TLR4/NF-κB, TNF-α, IL-1β), metabolic/kinase biomarkers (SIRT1, AMPK, PI3K, AKT), and histopathology/immunohistochemistry (mTOR, MYD88, Nrf2). Remogliflozin was associated with lower serum creatinine, urea, and uric acid, with endpoint-specific differences between doses. Remo was associated with higher renal Nrf2, HO-1, SIRT1, and p-AMPK, and lower MDA, TLR4, NF-κB, TNF-α, IL-1β, PI3K, and AKT. Histopathology and IHC showed associations with reduced tissue injury, lower mTOR and MYD88 immunoreactivity, and increased Nrf2 staining. While the 50 mg/kg group showed changes in more markers, this does not establish uniform dose superiority or a formal dose-response relationship; at 25 mg/kg, effects differed among AMPK-related endpoints. Direct 25-versus-50 mg/kg comparisons were included in the Tukey-Kramer analysis for each endpoint. No pharmacokinetic measurements or formal dose-response analyses were performed. In this exploratory model, remogliflozin was associated with attenuation of TAA-induced renal injury and modulation of related biomarkers. Causal mechanisms remain to be confirmed by targeted intervention studies. Findings are limited to young male Wistar rats and should not be generalized to other populations or clinical settings. Remogliflozin warrants further preclinical investigation in TAA-associated renal injury.