新药TJ0711对肾血管性高血压大鼠的肾脏保护作用及机制

Renal Protective Effect of TJ0711 on Renovascular Hypertensive Rats and Mechanism

目的研究新药TJ0711对肾血管性高血压大鼠的肾脏保护作用及可能的作用机制。方法 36只Wistar大鼠随机分成6组,1组为假手术组,其余5组均为二肾一夹(two-kidney one-clip,2K1C)肾血管性高血压模型,再分为模型组、卡维地洛组、TJ0711低剂量组、TJ0711中剂量组和TJ0711高剂量组,每组各6只。给药8周后处死大鼠,检测血清尿素氮(BUN)和肌酐(Scr)、尿蛋白/尿肌酐(urine protein/creatinine ratio)和血清一氧化氮(nitric oxide,NO)水平。取夹侧肾组织行免疫组化检测肾组织中缺氧诱导因子1α(HIF-1α)和Vasohibin的表达。Western blot法测定肾组织中内皮型一氧化氮合酶(eNOS)、HIF-1α和Vasohibin的表达。结果与模型组相比,治疗组各组大鼠血肌酐无明显变化,但血清尿素氮和尿蛋白/尿肌酐水平明显降低,同时血清NO明显增多(P<0.05),eNOS蛋白表达亦增加(P<0.05)。免疫组化和Western blot检测均显示,与模型组相比,TJ0711低、中剂量组HIF-1α和Vasohibin表达减少(均P<0.05),而卡维地洛和TJ0711高剂量组无明显变化。结论新药TJ0711能明显降低2K1C肾血管性高血压大鼠的蛋白尿和尿素氮水平,其对肾血管性高血压大鼠肾脏的保护机制可能与其上调eNOS表达、增加NO,同时下调HIF-1α和Vasohibin表达有关。

Objective To investigate renal protective effects of TJ0711 on rat two-kidney one-clip hypertension model and the mechanism. Methods Thirty-six Wistar rats were randomly divided into six groups：sham group, and five groups of renovascular hypertension（model group,carvedilol group,low dose of TJ0711 group,moderate dose of TJ0711 group,and high dose of TJ0711 group）, n= 6 each. Renovascular hypertension model was established by two-kidney one-clip method and the rats were sacrificed eight weeks after administration. Urea nitrogen,ereatinine,urinary protein/urine creatinine,and serum NO were determined. HIFla and Vasohibin were detected from renal cortical tissue by using immunohistochemical staining,and eNOS, HIF-la and Vasohibin by using Western blot. Results There was no significant change in creatinine. Compared to model group, urea nitrogen and urinary protein/urine creatinine were decreased in groups of intervention,while serum NO and eNOS protein were increased（P〈0.05）. Compared to model group, HIF-la and Vasohibin were down-regulated in low dose of TJ0711 and moderate dose of TJ0711 groups（P〈0. 05）. HIF-la and Vasohibin were slightly up-regulated in high dose of TJ0711 group（P 〉0.05）. Conclusion TJ0711 can obviously reduce urinary protein and urea nitrogen in rat model of two-kidney one-clip renovascular hypertension probably by up-regulating the expression of eNOS and NO,and simultaneously down-regulating the expression of HIF-la and Vasohibin.