AngⅡ是高血压发生过程中的关键分子。越来越多的证据表明AngⅡ主要通过激活肾内RAS而导致高血压的发生。肾素原受体是最新发现的组织RAS的新成员,可调节肾素活性并受AngⅡ刺激调节。前期研究发现，在AngⅡ诱导的高血压模型中，PRR和肾素的表达明显上调，同时肾脏局部应用PRR抑制多肽PRO20可明显阻断AngⅡ诱导的高血压及肾损伤。免疫荧光分析发现PRR主要在肾脏血管平滑肌表达。这些结果提示肾脏血管PRR是肾脏RAS和肾脏血管稳态调节中的关键调控因子。鉴于此，我们推测肾脏血管PRR通过影响局部RAS活性以及血管稳态与重构，从而决定AngII诱导高血压的发生以及肾脏损伤。因此，为明确肾脏血管PRR的作用，本项目将运用PRR抑制多肽PRO20及肾脏血管平滑肌PRR基因敲除小鼠等手段，全方位研究PRR在肾脏血管稳态与重构及高血压发病过程中的作用，为高血压的肾机制及治疗靶点提供新的视点。

AngiotensinⅡ (AngⅡ) plays an essential role in the pathogenesis of human hypertension. Increasing evidence suggests that AngⅡ induces hypertension primarily by triggering the intrarenal renin-angiotensin system (RAS) that results in generation of endogenous AngⅡ. Along this line, prorenin receptor (PRR), a newly discovered component of tissue RAS and activator of renin and prorenin, its expression is stimulated by AngⅡ. Preliminary studies demonstrated that AngⅡ induced hypertension along with the elevated PRR and renin expression were all blunted by PRR or COX-2 inhibition. By the way, Immunofluorescence staining of PRR in kidney shown high expression in vascular smooth muscle. Based on these observations, we hypothesize that PRR play a key role in regulation of renal RAS and vascular homeostasis. To address the function of renal vascular PRR, we propose to employ a newly developed decoy peptide PRO20 and renal vascular smooth muscle specific PRR KO mice to study its impact on renal RAS, renal hemodynamics and the AngII induced hypertension and vascular remodeling. Additionally, we will employ a luciferase knock-in mouse and primary culture VSMC to study the effect of AngⅡ infusion on renal COX-2 transcriptional activity and the relationship of PRR and COX2/PGE2/EP4 signal pathway. This proposal is expected to offer novel insight into the role of renal vascular PRR, the renal mechanism of AngⅡ induced hypertension and also to provide new antihypertensive targets.