Study on the effect and mechanism of taxifolin on ameliorating cisplatin-induced acute kidney injury in mice through peroxisome proliferator-activated receptor γ coactivator-1α-mediated antioxidant pathway / 中华肾脏病杂志

ABSTRACT

Objective:To explore the effect and mechanism of taxifolin (TAX) on ameliorating cisplatin-induced renal oxidative damage.Methods:(1) Forty male C57BL/6 mice were divided into 4 groups control group ( n=10), TAX group ( n=10), cisplatin group ( n=10) and cisplatin+TAX group ( n=10). The weight of mice in each group was measured. The level of serum creatinine (Scr) and blood urea nitrogen (BUN) was analyzed. Kidney histopathological change in mice was analyzed by HE staining. The pro-inflammatory cytokines levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured by enzyme linked immunosorbent assay. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) were measured by multifunctional microplate reader. The expression of inflammatory factors, antioxidant genes, and peroxisome proliferator-activated receptor γ coactivator-1α ( PGC- 1) mRNA were measured by real-time PCR. Evaluation of mitochondrial function by measuring ATP level and mtDNA content. Determination of AMP-activated protein kinase (AMPK) and phosphorylated AMPK protein expression by Western blotting. (2) Evaluate the effect of taxifolin on chemotherapy of cisplatin by establishing Lewis lung cancer transplantation tumor C57BL/6 mice model. Results:Compared with the control group, the weight of the mice in the TAX group was not significantly reduced ( P>0.05), and there was no obvious kidney damage ( P>0.05), indicating that oral TAX had good safety. Compared with the cisplatin group, TAX could significantly delay cisplatin-induced the weight loss of mice, reduce the levels of Scr and BUN, and alleviate the pathological changes of kidney tissue (all P<0.05). TAX could reduce the levels of serum inflammatory factors IL-6 and TNF-α and the expression of renal inflammatory factors IL- 6, TNF- α and IL- 1β mRNA induced by cisplatin in mice (all P<0.05). TAX could significantly reduce the levels of ROS and MDA, and increase the activities of SOD, CAT and GSH in cisplatin-induced acute kidney injury mice (all P<0.01). Meanwhile, TAX could up-regulate the mRNA expression of UCP2, SOD2, CAT antioxidant genes and PGC- 1α in the kidneys of mice with acute kidney injury induced by cisplatin, and increase the levels of ATP and mtDNA in cisplatin-induced acute kidney injury mice (all P<0.01). Western blotting results showed that TAX significantly promoted the expression of phosphorylated AMPK protein in cisplatin-induced acute kidney injury mice ( P<0.01). In addition, through the establishment of Lewis lung cancer transplantation tumor C57BL/6 mice model, it was found that TAX had no significant effect on the anti-tumor efficacy of cisplatin. Conclusions:TAX can ameliorate cisplatin-induced renal oxidative damage, and its mechanism may be related to the activation of AMPK/PGC-1α pathway.