Tetramethylpyrazine Ameliorates Cisplatin-Induced Acute Kidney Injury by Inhibiting Mitochondrial Fission and Renal Tubular Epithelial Cell Apoptosis through PGC-1α Pathway / 世界科学技术-中医药现代化

ABSTRACT

Objective To investigate the effects of tetramethylpyrazine(TMP)on acute kidney injury(AKI)induced by cisplatin(Cis)and its related mechanisms.Methods Sixty SPF male C57BL/6J mice were randomly divided into control group(Ctl),TMP group,Cis-induced AKI model group(Cis group)and TMP treated AKI model group(Cis+TMP group).The contents of BUN and Scr were detected,and the apoptosis of renal tissue was detected by TUNEL staining.The structural changes of mitochondria in renal cortex of each group were observed by transmission electron microscope,and the expression of ROS in renal tissue was detected by DHE staining.The expression of PGC-1α and the phosphorylation of Drp1(p-Drp1Ser637/Drp1)in renal tissue were detected by Western blotting assay.Proximal renal tubule epithelial cell line HK-2 was cultured in vitro and divided into Ctl group,TMP group,Cis group and Cis+TMP group.Proliferation activity of cells in each group was detected by CCK-8 assay,apoptosis was detected by Annexin V-FITC/PI method,ROS expression and mitochondrial membrane potential were detected by DCFH-DA fluorescence probe and JC-1 staining.The expression of PGC-1α and p-Drp1Ser637/Drp1 were detected by Western blotting assay.Results Compared with Ctl group,the contents of BUN and Scr in Cis group and Cis+TMP group were significantly increased(P<0.05),cell apoptosis of renal tubular and the damage of renal cortical mitochondrial structure were significantly increased(P<0.05).However,the expression of PGC-1α protein and p-Drp1Ser637/Drp1 ratio in renal tissue were significantly decreased(P<0.05),and no significant changes were observed in TMP group(P>0.05).Compared with Cis group,the change trend of above detection indexes in Cis+TMP group was significantly decreased(P<0.05).Compared with HK-2 cells in Ctl group,the proliferation activity,mitochondrial membrane potential,PGC-1α protein expression and p-Drp1Ser637/Drp1 ratio of Cis group and Cis+TMP group were significantly decreased(P<0.05),while the apoptosis ratio of Cis and Cis+ TMP group was significantly decreased(P<0.05).The ROS expression and Drp1 protein expression in mitochondria were significantly increased(P<0.05),but no significant changes were observed in TMP group(P>0.05).Compared with Cis group,the change trend of above detection indexes in Cis+TMP group was significantly decreased(P<0.05).Conclusions TMP can ameliorate CIS-induced apoptosis and mitochondrial damage in renal tubular epithelial cells in vitro and in vivo,which may be related to PGC-1α pathway.