Interaction of PGE2 and intrarenal RAS in AngII-induced hypertension

描述（由申请人提供）：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），特别是集管（CD）中的肾素反应导致内源性AngII的产生，从而诱发高血压。沿着这条线，（pro）肾素受体（PRR）是一种新发现的组织RAS成分，也是肾素和prorentin的激活剂，在CD中与肾素共定位，其表达类似地受到AngII的刺激。初步研究表明，COX-2抑制或EP4拮抗均可使血管内皮素诱导的高血压伴PRR升高和肾素表达减弱。另一方面，在IMCD细胞中，PRR的过表达可增加COX-2的表达。基于这些观察结果，我们假设COX-2/EP4和PRR/renin在CD中的表达/活性相互正向调节，形成一个恶性循环，放大局部肾素反应，最大限度地产生AngII，然后在AngII诱导的高血压期间激活ENaC。设计了三个具体目标来检验一般假设。Aim 1使用CD特异性EP4敲除模型来验证CD EP4受体的激活导致PRR、肾素和ENaC的顺序激活，最终导致AngII输注后血压升高的假设。目的2使用cd特异性肾素过表达或缺失的小鼠来验证远端肾元局部RAS活性积极影响肾前列腺素合成的假设。肾COX-2转录活性的改变是通过注射AngII后荧光素酶敲入报告小鼠的体内成像来监测的。目的3采用一种新型的PRR诱骗肽结合髓内输注技术来验证肾髓质PRR抑制在AngII输注过程中减弱局部肾素反应和血压的假设。该研究结果有望为血管内皮素诱导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治疗潜力。

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.