【作者】 杨娟；

【导师】 姚颖；

【作者基本信息】 华中科技大学 ， 内科学， 2013， 硕士

【摘要】 目的研究新药TJ0711（一种新型β1和α1肾上腺受体阻滞剂）对自发性高血压大鼠（SHR）的肾脏保护作用及可能的作用机制。方法自发性高血压大鼠（SHR）35只，随机分为以下5组：对照组（生理盐水，20mg/kg/day），TJ0711低剂量组（TJ0711，10mg/kg/day），TJ0711中剂量组（TJ0711，20mg/kg/day），TJ0711高剂量组（TJ0711，40mg/kg/day）和卡维地洛组（卡维地洛，20mg/kg/day），每组各7只，灌胃给药。采用无创大鼠尾动脉血压测定法测定给药前、后血压，同时留取24h尿样。给药7周后处死大鼠，采用全自动生化分析仪检测血清尿素氮（BUN）、肌酐（Scr）、胱抑素C（Cystatin C）和C反应蛋白（CRP）等，同时测定24h尿总蛋白和白蛋白；取肾皮质行HE及PAS等染色；采用免疫组织化学和Western blot法检测肾皮质血红素氧合酶-1（HO-1）、内皮型一氧化氮合酶（eNOS）、缺氧诱导因子-1α（HIF-1α）和Vasohibin-1等蛋白的表达；采用ELISA法检测血中白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白介素-10（IL-10）和脂联素（Adiponectin）的水平。结果TJ0711各组的降压效果与卡维地洛组相当；与对照组相比，各治疗组大鼠肾脏病理学改变有所好转，24h尿白蛋白和总蛋白明显降低（p<0.05），而血清尿素氮（BUN）、肌酐（Scr）、胱抑素C（Cystatin C）和C反应蛋白（CRP）无明显变化；血浆IL-1β和TNF-的水平明显降低（p<0.05），而血浆IL-10和脂联素水平明显升高（p<0.05）；Western Blot和免疫组化结果显示TJ0711和卡维地洛均能上调eNOS、HO-1和HIF-1α的表达，同时TJ0711能下调Vasohibin-1的表达。与卡维地洛组相比，TJ071120组上述作用更为明显。结论新药TJ0711具有和卡维地洛相似的降压疗效，但其肾脏保护作用优于卡维地洛，这种保护作用可能源于其更强的α1受体阻滞功能。其作用机制主要与其减轻慢性炎症反应和氧化应激有关，TJ0711有望成为新的具有更好肾脏保护作用的抗高血压药物。更多还原

【Abstract】 Objective To investigate the renal protective effects and the mechanisms of TJ0711(anovel vasodilatory β-blocker with a1:1ratio for the β1/α1blocking activities) againsthypertension induced renal injury on SHR.Methods Thirty five SHR (spontaneously hypertensive rats) were randomly divided intofive groups: control (saline,20mg/kg/day), carvedilol (carvedilol,20mg/kg/day), TJ071110(TJ0711,10mg/kg/day), TJ071120(TJ0711,20mg/kg/day) and TJ071140(TJ0711,40mg/kg/day). Tail artery systolic blood pressure before and after drug administration wasmonitored weekly. Serum samples,24h urine and kidneys tissue were collected. Renalfunction was evaluated by blood urea nitrogen (BUN), serum creatinine (Scr), Cystatin C,C-reactive protein (CRP),24h total urine protein and24h urine albumin. The pathologicalchanges of kidney damage were revealed by Periodic Acid-Schiff (PAS) staining andHematoxylin-Eosim (HE) staining. The location and expression of Hypoxia-InducibleFactor-1α (HIF-1α), Vasohibin-1, Hemo Oxygenase-1(HO-1) and Endothelial Nitric OxideSynthase (eNOS) of renal tissue was detected by immunohistochemistry and Western blot.The levels of TNF-α, IL-1β, IL-10and Adiponectin in serum were measured by ELISA. Results TJ0711possesses similar potency for control of blood pressure as that of carvedilol.Compared to the control group,24h urine protein and histopathological changes wereobviously attenuated in TJ071120group. Serum IL-1β, TNF-α levels were significantlylower (p <0.05), IL-10and adiponectin levels were markedly increased (p<0.05) in TJ071120group. Immunohistochemistry and Western blot showed medium does of TJ0711canup-regulated HIF-1α, eNOS and HO-1expression and down-regulated vasohibin-1expression (p<0.05).Conclusion TJ0711is more effective to protect SHR against hypertension induced renalinjury as compared with carvedilol. Its protective effect is related to enhancing eNOSexpression through suppressing inflammatory cytokine secretion and attenuatingVasohibin-1expression to prevent HIF-1α from signal-induced degradation by whichpromotes HO-1expression to protect SHR against oxidative stress.更多还原