Zhao Gang, Zhao Hong, Tu Ling, Xu Xizhen, Zheng Changlong, Jiang Meihua, Wang Peihua, Wang Daowen
The Institute of Hypertension and Cardiovascular Division, Department of Internal Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Huazhong Univ Sci Technolog Med Sci. 2010 Feb;30(1):48-54. doi: 10.1007/s11596-010-0109-1. Epub 2010 Feb 14.
Tubulointerstitial fibrosis (TIF) is a common pathological feature of end-stage kidney disease. Previous studies showed that upregulation of TGFbeta1 notably contributed to the chronic renal injury and irbesartan halted the development of TIF in rats with 5/6 renal mass reduction. This study was to investigate the effects of irbesartan on chronic TIF and the mechanism involved TGFbeta1 in the rodent model of chronic renal failure involving 5/6 nephrectomy. The results showed that irbesartan significantly attenuated the rise in blood pressure and tubulointerstitial injury observed in this model. Masson staining of the renal tissue revealed that there appeared severe renal tubule atrophy and fibrosis in operation group, but the lesion was attenuated mostly in irbesartan-treated group. Immunohistochemistry showed that irbesartan treatment apparently decreased the protein expression of TGFbeta1 which was up-regulated in operation groups. Western blot showed that irbesartan treatment down-regulated the expression of TGFbeta1, phosphorylated smad2 (p-smad2), AT1R and phosphorylated p38 (p-p38) MAPK, but significantly up-regulated the protein expression of smad6 as compared with operation group. These findings suggest that irbesartan attenuates hypertension and reduces the development of TIF in rats with 5/6 renal mass reduction via changes in the expression of these proteins at least including smad6, TGF-beta1, p-smad2, AT1 and p-p38 MAPK.
肾小管间质纤维化（TIF）是终末期肾病的常见病理特征。先前的研究表明，转化生长因子β1（TGFbeta1）的上调显著促成了慢性肾损伤，而厄贝沙坦可阻止5/6肾切除大鼠TIF的发展。本研究旨在探讨厄贝沙坦对慢性TIF的影响以及TGFbeta1在5/6肾切除的慢性肾衰竭啮齿动物模型中的作用机制。结果显示，厄贝沙坦显著减轻了该模型中观察到的血压升高和肾小管间质损伤。肾组织的Masson染色显示，手术组出现严重的肾小管萎缩和纤维化，但在厄贝沙坦治疗组中病变大多减轻。免疫组织化学显示，厄贝沙坦治疗明显降低了手术组中上调的TGFbeta1蛋白表达。蛋白质印迹法显示，与手术组相比，厄贝沙坦治疗下调了TGFbeta1、磷酸化的Smad2（p-smad2）、血管紧张素Ⅱ1型受体（AT1R）和磷酸化的p38丝裂原活化蛋白激酶（p-p38）的表达，但显著上调了Smad6的蛋白表达。这些发现表明，厄贝沙坦通过改变至少包括Smad6、TGF-β1、p-smad2、AT1和p-p38丝裂原活化蛋白激酶在内的这些蛋白质的表达，减轻了5/6肾切除大鼠的高血压并减少了TIF的发展。
