Dapagliflozin treatment ameliorates oxidative stress, apoptosis and inflammation in tenofovir-induced nephrotoxicity in rats

Tenofovir disoproxil fumarate is a widely prescribed component in antiretroviral therapy regimes frequently associated with nephrotoxicity. Dapagliflozin, an SGLT2 inhibitor, is primarily used as a hypoglycemic agent but is increasingly recognized for its pleiotropic protective effects. To investigate whether dapagliflozin could mitigate tenofovir-induced nephrotoxicity, Wistar rats were randomly assigned to four groups: Control- received a standard diet for 45 days, TDF- received a standard diet added with tenofovir (300 mg/kg food) for 45 days, DAPA- received a standard diet for 45 days added with dapagliflozin (20 mg/kg food) in the last 15 days, and TDF + DAPA- received a standard diet added with tenofovir for 45 days and dapagliflozin in the last 15 days. Dapagliflozin administration restored glomerular filtration rate, improved renal hemodynamic parameters and maintained the adequate balance of TBARS/GSH levels through the modulation of SIRT1/Nrf2/HO-1 signaling pathway and mitochondrial enzymatic antioxidant system-related markers. Furthermore, dapagliflozin treatment reduced inflammatory response and apoptotic cell death, marked by increased Bcl-2 expression and decreased levels of TLR4, NF-κB, pro-inflammatory cytokines, Bax, cytochrome c, and caspase-3. Dapagliflozin holds multifaceted renoprotective effects potentially offering a therapeutic strategy to slow the progression of kidney injury in tenofovir-induced nephrotoxicity.