目的:探讨达格列净和坎地沙坦联用对糖尿病肾脏尿液浓缩调节的影响。方法:尾静脉注射链脲佐菌素(STZ)制备糖尿病大鼠,以达格列净1mg/(kg·d)及坎地沙坦2mg/(kg·d)的剂量灌胃给药7d,代谢笼实验收集24h尿,监测血糖、尿糖、血Na~+,K~+,Cl~-浓度、24h尿量、尿渗透压;分离肾皮质、外髓、内髓尖端、内髓基底段,Western Blot检测外髓钠-钾-氯共转运蛋白(NKCC2)、内髓尿素转运蛋白A1(UT-A1)、内髓水通道蛋白2(AQP2)蛋白表达。结果:与未治疗糖尿病组相比,达格列净单用,达格列净和坎地沙坦联用分别降低血糖47%和42%,而三组尿糖浓度(mmol/L)相当(513.3±22.8 vs 569.2±18.7 vs 533.3±34.6),与正常对照组相比,三组糖尿病大鼠出现多尿、尿渗透压降低,但与未治疗糖尿病组相比,两治疗组都减轻了多尿程度[24h尿量(ml):135±19 vs 83±5 vs 70±13,P<0.05],也改善了尿渗透压(mOsm/kg H_2O)(751±41 vs 1 067±31 vs 1 189±154,P<0.05)。Western Blot分析显示糖尿病大鼠肾组织内NKCC2、UT-A1及AQP2较正常对照组明显升高。与未治疗糖尿病组相比,达格列净治疗进一步升高了内髓尖端UT-A1蛋白表达。达格列净和坎地沙坦联用组则进一步上调了内髓尖端UT-A1和外髓NKCC2蛋白表达。结论:达格列净和坎地沙坦联用进一步上调了糖尿病肾髓质UTA1和NKCC2蛋白表达,较达格列净单用进一步减轻高尿糖渗透性利尿程度,这提示钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂和血管紧张素Ⅱ受体抑制剂(ARB)联用有利于防止单用SGLT2抑制剂所致的容量丢失和电解质紊乱
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