Ezetimibe ameliorates cisplatin‐induced nephrotoxicity: A novel therapeutic approach via modulating AMPK/Nrf2/TXNIP signaling

Abstract Cisplatin (Cis) is among the most powerful antineoplastic medications, nevertheless, its serious side effects; particularly nephrotoxicity designates a major concern. Previous studies reported that ezetimibe (Eze), a well‐known antihyperlipidemic drug, exerts additional trivial pharmacological effects. In this work, we displayed Eze as an intriguing protective candidate in a cisplatin‐induced nephrotoxicity rat model through AMPK activation. Eze (10 mg/kg, p.o.) was administered for two weeks and Cis (10 mg/kg, i.p.) was administered on the 10th day to induce nephrotoxicity in male Wistar rats. Treatment with Eze greatly augmented the phosphorylation of adenosine 5′‐monophosphate‐activated protein kinase (AMPK) and the antioxidant regulator; nuclear factor erythroid 2‐related factor 2 (Nrf2), thus, mitigating oxidative injury through induction of the antioxidant enzymes, such as heme oxygenase‐1 (HO‐1) and glutathione reductase (GR). As well, Eze relieved inflammation by reducing protein expression of thioredoxin‐interacting protein (TXNIP) and nucleotide‐binding domain‐like receptor protein 3 (NLRP3), which led to a decrease in the release of caspase‐1, in addition to, the inflammatory markers IL‐18 and IL‐1 β. Besides, Eze ameliorated apoptosis in the renal cells through inhibiting the phosphorylated Apoptosis signal‐regulating kinase‐1(p‐ASK1), caspase‐3 and reducing Bax/Bcl2ratio. Correspondingly, histopathological examination corroborated the previous biochemical findings. Collectively, Eze exerts significant renal protection against Cis‐induced nephrotoxicity via antioxidant, anti‐inflammatory and anti‐apoptotic pathways that are probably mediated, at least partly, via activating AMPK/Nrf2/HO‐1 pathway and conquering both TXNIP/NLRP3 inflammasome and TXNIP/ASK1 signaling pathways. To confirm the protective effect of Eze via AMPK‐activation, an AMPK‐inhibitor, dorsomorphin (Dors), when co‐administered with Eze abolished its protective effect.