Abstract
Aims: This study aimed to elucidate the role and function of roxadustat, a small molecule hypoxia-inducible factor (HIF) stabilizer, on cisplatin-induced acute kidney injury (AKI) in vivo and in vitro. Methods: We investigated the effects of roxadustat (10 mg/kg) in a cisplatin-induced AKI model in mice. After a 48-hour pretreatment with the intraperitoneal injection of roxadustat, cisplatin was administered at a dose of 20 mg/kg by intraperitoneal injection. We also examined the role of roxadustat (10 μM) on HK-2 cells stimulated by cisplatin (20 μg/mL). Results: Pretreatment with roxadustat significantly improved kidney function in the AKI model, as evidenced by reductions of Scr and BUN, and alleviated cisplatin-induced kidney morphology lesions. Roxadustat also remarkably decreased the expression of KIM-1 and NGAL. Furthermore, roxadustat significantly abolished the expression of Bax and cleaved caspase 3, two apoptosis marker proteins. Mechanistically, our study demonstrated that roxadustat could alleviate the deficiency of fatty acid oxidation (FAO) induced by cisplatin, as evidenced by the improvement of lipid accumulation and metabolic disorders in the roxadustat-treated group. Moreover, roxadustat effectively blocked mitochondrial damage, as evidenced by reduced mitochondrial swelling and fragmentation in the roxadustat-treated group. Simultaneously, roxadustat also partially rescued the expression of mitochondrial fusion proteins, including OPA1, MFN1, and MFN2. In vitro, roxadustat also effectively alleviate injury, apoptotic responses, FAO disorders, mitochondrial damage caused by cisplatin. Conclusion: We demonstrated that roxadustat exerts a protective role in cisplatin-treated mice and HK-2 cells, which might be due to amelioration of FAO deficiency and suppression of mitochondrial damage.