Telmisartan and Nicorandil Attenuate Polymyxin B-Induced Renal Injury by Modulating NrF2/NQO1, FAS/FASL Signaling, and Mitigation of P53, Cyt-C, and Caspase-3

Polymyxin B (PMB) is widely used as a last-line antibiotic for treating serious infections caused by multidrug-resistant Gram-negative bacteria. However, its clinical use is restricted by significant nephrotoxicity, which limits dosing flexibility and compromises therapeutic efficacy. The aim of this study was to evaluate the potential nephroprotective effects of telmisartan (TMS) and nicorandil (NIC) in rats treated with polymyxin B (PMB). Rats were randomly allocated into four groups. Normal control; PMB (12 mg/kg/day, S.C. for one week); TMS + PMB (10 mg/kg/day TMS orally (p.o.) for two weeks); and NIC + PMB (3 mg/kg/day NIC, i.p. for two weeks). Both drugs were administered one hour prior to PMB for one week and continued for an additional week. At the end of the treatment period, animals were anesthetized, and blood and kidney tissue samples were collected for histological and immunohistochemical analyses, as well as assessments of renal function, oxidative stress markers, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptotic biomarkers. The findings demonstrated that both telmisartan and nicorandil significantly improved renal function and attenuated oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis-related markers. Histopathological findings supported these results. The renoprotective effects of telmisartan and nicorandil were mediated through modulation of the Nrf2/NQO1 antioxidant pathway and FAS/FASL apoptotic signaling, along with downregulation of renal expression of p53, cytochrome c, and caspase-3. These observations clearly indicate the protective role of both agents against PMB-induced nephrotoxicity.