ACE2与TGF-β1-Smad3信号对高盐介导高血压血管纤维化的调控作用

High salt-intake causes hypertensive vascular fibrosis. Our previous studies have demonstrated that high dietary salt could lead to hypertension and the fibrosis of aorta, carotid artery and mesenteric artery in Wistar rats. Angiotensin II (Ang II) is critically involved in the pathogenesis of vascular fibrosis through influencing TGF-β1/Smad3 signaling pathway. Angiotensin converting enzyme 2 (ACE2) is a endogenous enzyme of specifically degrading AngII，but its underlying mechanisms involved in hypertensive vascular fibrosis are unclear. The recent studies have showed that activation of miRNA-21 and/or inactivation of miRNA-29b participates in myocardial fibrosis and kidney fibrosis mediated by TGF-β1-Smad3 signaling pathway. Therefore, we propose to apply normal and DOCA salt-sensitive hypertensive rats and gene overexpression or knockout technology, and deeply investigate the activation of TGF-β1/Smad3 is associated with downregulation of ACE2, and Smad3 regulates the expressions of miR-21 and(or) miR-29b to cause vascular fibrosis in vitro and in vivo. We want to clarify the mechanism of ACE2 regulating TGF-β1-Smad3 signaling and miR-21/miR-29b in hypertensive vascular fibrosis caused by high salt. The study will provide theoretical basis and new targets for the prevention and treatment of hypertensive vascular fibrosis induced by high-salt diet.

高盐饮食诱导高血压血管纤维化。我们前期研究表明，长期高盐饮食介导Wistar 大鼠血压升高、主动脉和颈动脉及肠系膜动脉纤维化，血管紧张素II（Ang II）可通过影响TGF-β1-Smad3信号在高盐致高血压血管纤维化中起关键作用。血管紧张素转化酶2（ACE2）是内源性降解Ang II的特异性催化酶，但它对高血压血管纤维化作用及机制不清楚。新近发现，miRNA-21激活和/或miRNA-29b失活参与TGF-β1-Smad3通路介导的心肾纤维化。本项目拟采用正常和DOCA盐敏感型高血压大鼠模型及基因敲除或过表达技术，从整体和细胞水平进行研究，证实高盐通过下调ACE2基因使TGF-β1-Smad3激活、Smad3信号调控miRNA-21和/或miRNA-29b介导高血压血管纤维化。为确立ACE2及miRNA-21/miRNA-29b作为高盐诱导高血压血管纤维化防治的新靶点提供科学依据。