Endothelin receptor antagonist combined with a calcium channel blocker attenuates renal injury in spontaneous hypertensive rats with diabetes

内皮素受体阻断剂合用钙通道阻滞剂能抑制糖尿病高血压大鼠的肾脏损害(英文)

OBJECTIVE: To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes. METHODS: Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week. RESULTS: Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters. CONCLUSION: Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.

目的 观察非选择性内皮素受体阻断剂Bosentan合用长效钙通道阻滞剂Amlodipine对糖尿病高血压大鼠的肾脏保护作用 ,并与血管紧张素转换酶抑制剂Cilazapril进行比较。方法 将雄性自发性高血压大鼠 (SHR) (7周龄 )建成链脲佐菌素诱导的糖尿病高血压模型 (SHR DM) ,分Bosentan+Amlodipine组、Amlodipine组、Cilazapril组和非治疗组。WKY和SHR大鼠分别作为正常对照组和高血压对照组。4周后观察平均动脉血压、肾功能、内皮素和血管紧张素Ⅱ的水平、以及肾脏细胞外基质和转化生长因子 (TGF) β1的改变。结果 与WKY对照组相比 ,SHR DM大鼠和SHR大鼠的平均动脉压显著升高 ,三种治疗方法都能使其降至正常水平。然而在SHR DM大鼠中 ,2 4小时尿蛋白排出增加、肌酐清除率下降、以及血浆和肾组织中内皮素和血管紧张素Ⅱ的增加仅Bosentan +Amlodipine和Cilazapril治疗能显著缓解。同样 ,这两种治疗可有效抑制肾内TGFβ1蛋白的过度表达 (Westernblot) ,并减少Ⅳ型胶原、Laminin和Fibronectin的积聚 (免疫组化 )。Amlodipine单独治疗对上述各项指标无显著影响。结论 Bosentan合用Amlodipine的肾脏保护作用类似于Cilazapril,故有可能作为一种有力的治疗手段 ,通过减少肾脏TGFβ1的表达而缓解糖尿病高血压时的肾脏损害?