Interaction of PGE2 and intrarenal RAS in AngII-induced hypertension

说明(申请人提供)：血管紧张素II(AngII)在人类高血压的发病机制中起着重要作用。越来越多的证据表明，Angii主要通过触发肾内肾素-血管紧张素系统(RAS)，特别是集合管(CD)中的肾素反应而导致内源性Angii的产生，从而导致高血压。沿着这条线，(Pro)肾素受体(PRR)是新近发现的组织RAS的组成部分，它是肾素和前肾素的激活剂，与肾素在CD中共存，其表达与血管紧张素Ⅱ刺激的表达相似。初步研究表明，血管紧张素Ⅱ诱导的高血压以及PRR和肾素表达的升高均被COX-2抑制或EP4拮抗所钝化。另一方面，在IMCD细胞中，PRR的过表达可增加COX-2的表达。基于这些观察，我们假设COX-2/EP4和PRR/肾素在CD中正向调节彼此的表达/活性，形成一个恶性循环，在血管紧张素Ⅱ诱导的高血压过程中放大局部肾素反应，从而最大限度地产生血管紧张素Ⅱ，进而激活ENaC。已经设计了三个具体的目标来检验这一普遍假设。目的1采用CD特异性EP4基因敲除模型，验证CDEP4受体激活导致PRR、肾素和ENaC顺序激活的假说，最终导致血管紧张素转换酶抑制剂(Angii)引起的血压升高。目的利用CD特异性肾素过度表达或缺失的小鼠，验证肾远端肾单位局部RAS活性正向影响肾脏前列腺素合成的假说。肾COX-2转录活性的变化是通过注射血管紧张素Ⅱ后的荧光素酶敲入报告鼠的体内成像来监测的。目的3采用一种新的PRR诱骗多肽与髓内输注技术相结合，验证抑制肾髓质PRR可降低局部肾素反应和血管紧张素转换酶(AngII)输注时血压的假说。这一提议带来的新信息有望为血管紧张素转换酶诱导性高血压的肾脏机制提供新的见解，并有助于确定新开发的PRR诱骗肽治疗高血压和肾脏疾病的潜力。

DESCRIPTION (provided by applicant): Angiotensin II (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), particularly the renin response in the collecting duct (CD) that results in generation of endogenous AngII. Along this line, (pro)renin receptor (PRR), a newly discovered component of tissue RAS and activator of renin and prorenin, is colocalized with renin in the CD and its expression is similarl stimulated by AngII. Preliminary studies demonstrated that AngII-induced hypertension along with the elevated PRR and renin expression was all blunted by COX-2 inhibition or EP4 antagonism. On the other hand, overexpression of PRR in IMCD cells is shown to increase COX-2 expression. Based on these observations, we hypothesize that COX-2/EP4 and PRR/renin positively regulate each other's expression/activity in the CD forming a vicious cycle which amplifies the local renin response for maximal AngII generation and then ENaC activation during AngII-induced hypertension. Three specific aims have been designed to test the general hypothesis. Aim 1 uses CD-specific EP4 knockout model to test the hypothesis that the activation of CD EP4 receptor results in sequential activation of PRR, renin, and ENaC, ultimately leading to elevation of BP in response to AngII infusion. Aim 2 uses mice with CD-specific overexpression or deletion of renin to test the hypothesis that the activity of local RAS n the distal nephron positively affects renal prostaglandin synthesis. The alteration of renal COX-2 transcriptional activity is monitored by in vivo imaging of luciferase knock-in reporter mice following AngII infusion. Aim 3 employs a novel PRR decoy peptide coupled with the intramedullary infusion technique to test the hypothesis that inhibition of renal medullary PRR attenuates local renin response and BP during AngII infusion. New information resulted from this proposal is expected to offer new insight into the renal mechanism of AngII-induced hypertension and also help define the therapeutic potential of the newly developed PRR decoy peptide for treatment of hypertension and kidney disease.