奥美拉唑调控肾脏转运体OCT2和P-gp保护顺铂诱导的急性肾损伤

Study on omeprazole alleviated cisplatin-induced acute kidney injury via regulating the expression of renal transporter OCT2 and P-gp

目的:基于肾脏有机阳离子转运体OCT2、多药耐药相关蛋白P-糖蛋白(P-gp)研究奥美拉唑(OME)在大鼠及肾小管上皮细胞中拮抗顺铂诱导急性肾损伤的作用机制。方法:选择雄性SD大鼠随机分为空白组、模型组、药物组(1.8 mg·kg^(-1)和3.6 mg·kg^(-1))以及OME对照组。OME对照组和药物组连续5 d腹腔注射OME,药物组在第5 d腹腔注射顺铂(15 mg·kg^(-1)),模型组连续注射5 d生理盐水,第5天腹腔注射顺铂;空白组以上述相同时间注射生理盐水。各组在第7天取血和肾脏,通过HE染色和生化指标BUN、Cr检测观察肾组织损伤程度;MTT法检测肾小管上皮HK-2细胞存活率,Western blot检测OCT2和P-gp蛋白表达。结果:(1)OME能够减轻顺铂对HK-2细胞的损伤程度,提高细胞生存率;(2)与模型组比较,OME降低大鼠死亡率和肾脏肥大指数,改善肾小管空泡变性和炎性浸润,明显降低血清生化指标BUN和Cr水平;(3)Western blot实验结果表明在HK-2细胞和SD大鼠中,OME能够抑制肾脏OCT2的表达,上调外排转运体P-gp的表达。结论:OME能够在大鼠和细胞中有效保护顺铂诱导的急性肾损伤,其保护机制与OME抑制OCT2的表达,上调P-gp的表达有关。

OBJECTIVE To investigate the mechanisms of Omeprazole(OME)in antagonizing cisplatin-induced acute kidney injury in rats and renal tubular epithelial cells based on renal organic cation transporter OCT2 and multidrug resistance-associated protein P-glycoprotein(P-gp).METHODS Male SD rats were randomly divided into control group,model group,OME group(1.8 mg·kg-1 and 3.6 mg·kg-1)and OME control group.The control group and the OME group received intraperitoneal injection of OME for 5 days,and Cisplatin(15 mg·kg-1)was injected intraperitoneally on the 5 th day in the OME group.Model group:physiological saline was injected for 5 days in the model group,and cisplatin was injected intraperitoneally on the 5 th day.Control group:saline was injected at the same time as above.Blood and kidneys were collected from each group on the 7 th day.HE staining and biochemical parameters such as Cr and BUN were studied to evaluate the degree of renal tissue damage.MTT was used to test cell viability of HK-2 cells;Western Blot was used to determine protein expression of OCT2 and P-gp.RESULTS(1)OME could reduce the damage of cisplatin to HK-2 cells and improve the survival rate of cells;(2)Compared with the model group,OME reduced the mortality and renal hypertrophy index,improved tubular vacuolar degeneration and inflammatory infiltration,and significantly reduced the serum biochemical indicators BUN and Cr levels;(3)Western blot results showed that OME could inhibit the expression of OCT2 and up-regulate the expression of efflux transporter P-gp in HK-2 cells and SD rats.CONCLUSION can effectively protect cisplatin-induced acute kidney injury in rats and cells,and its protective mechanism is related to the inhibition of OCT2 expression and up-regulation of P-gp expression by OME.