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

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。

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

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 5th 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 5th day. Control group:saline was injected at the same time as above. Blood and kidneys were collected from each group on the 7th 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.