论文摘要
目的1.肾间质纤维化是多种肾脏疾病走向肾功能衰竭的共同病理过程。其发病机制迄今为止仍未得到确切的阐明。通常认为是多因素综合作用的结果。其中转化生长因子(Transforming growth factor-β,TGF-β)作为一种强效的致纤维化因子,在肾间质纤维化发生、发展的多个环节起作用,被认为是肾纤维化最重要的作用因子之一。Smads家族蛋白是新近发现的参与TGF-β超家族在细胞内信号传导的一族蛋白质,是TGF-β超家族成员参与生命活动的重要介质。本研究应用单侧输尿管结扎术(unilateral ureteral obstruction ,UUO)制作肾间质纤维化模型,并用体外人重组TGF-β1刺激人肾近端小管上皮细胞(human kidney proximal tubular epithelial cell, HKC),从整体、细胞和分子等不同水平,系统观察TGF-?/Smads信号传导途径在肾间质纤维化时细胞外基质的形成、细胞凋亡和增殖中的作用。2.他汀类药物在高脂血症治疗中的作用已被得到普遍的认可。大量实验和临床研究提示,他汀类药物对肾脏具有直接保护作用,能延缓肾脏病变的进展,且与其降脂作用无关。其可能机制包括调节增殖/凋亡平衡、炎性细胞因子的产生及细胞内信号传导通路。另外,肾素-血管紧张素-醛固酮系统(rennin angiotensin system, RAS)尤其是血管紧张素II(Ang II),在血流动力学调节和在肾硬化以及纤维化中起重要作用。Ang II是通过与其受体结合而进一步发挥作用的。缬沙坦(Valsartan)是近年来发现的一种血管紧张素II 1型受体拮抗剂(ang II type 1 receptor antagonism,AT1RA),从受体水平上阻断Ang II的生物学作用。它不但具有肯定且稳定的降压作用,而且对靶器官的保护作用也是独一无二的。在本实验中,我们分别选用辛伐他汀和缬沙坦进行干预研究,观察这些药物对TGF-β1、Smad2/3、p- Smad2/3和Smad7以及I型胶原蛋白和/或mRNA表达的影响,以探讨辛伐他汀和缬沙坦的肾脏保护作用机制。方法
论文目录
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