7-Hydroxycoumarin protects against cisplatin-induced acute kidney injury by inhibiting necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation

• Published in: Phytomedicine (Stuttgart) 2020-04, Vol.69, p.153202-153202, Article 153202
• Main Authors: Wu, Wei-Feng, Wang, Jia-Nan, Li, Zeng, Wei, Biao, Jin, Juan, Gao, Li, Li, Hai-Di, Li, Jun, Chen, Hai-Yong, Meng, Xiao-Ming
• Format: Article
• Language: English
• Subjects: 7-hydroxycoumarin; AKI; Cisplatin; Necroptosis; Proliferation; Sox9
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2020.153202

7-Hydroxycoumarin (7-HC), also known as umbelliferon, is commonly found in Chinese herbs (e.g. Eucommiae Cortex, Prunellae Spica, Radix Angelicae Biseratae). Previous laboratory studies have indicated that 7-HC has anti-inflammatory, anti-oxidative, and anti-tumor effects. Cisplatin is a widely used chemotherapeutic agent for cancer. Nephrotoxicity is one of the limiting side effects of cisplatin use. This study aimed to evaluate the renoprotective effect of 7-HC in a cisplatin-induced acute kidney injury (AKI) mouse model. AKI was induced in male C57BL/6 mice (aged 6–8 weeks) by a single intraperitoneal injection of cisplatin at 20 mg/kg. The mice received 7-HC at 30, 60, and 90 mg/kg intraperitoneally before or after cisplatin administration. Renal function, necroptosis, and cell proliferation were measured. Mechanisms underlying the reno-protective effect of 7-HC were explored in renal tubular epithelial cells treated with or without cisplatin. In-vivo experiments showed that 7-HC significantly improved the loss in kidney function induced by cisplatin, as indicated by lower levels of serum creatinine and blood urea nitrogen, in AKI mice. Consistent herewith, cisplatin-induced tubular damage was alleviated by 7-HC as shown by morphological (periodic acid–Schiff staining) and kidney injury marker (KIM-1) analyses. We found that 7-HC suppressed renal necroptosis via the RIPK1/RIPK3/MLKL pathway and accelerated renal repair as evidenced by the upregulation of cyclin D1 in cisplatin-induced nephropathy. In-vitro experiments showed that knockdown of Sox9 attenuated the suppressive effect of 7-HC on KIM-1 and reversed the stimulatory effect of 7-HC on cyclin D1 expression in cisplatin-treated HK-2 cells, indicating that 7-HC may protect against AKI via a Sox9-dependent mechanism. 7-HC inhibits cisplatin-induced AKI by suppressing RIPK1/RIPK3/MLKL-mediated necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation. 7-HC may serve as a preventive and therapeutic agent for AKI. [Display omitted]