Role of (pro)renin receptor in aldosterone signaling in the kidney

（Pro）肾素受体（PRR）在体外结合前肾素/肾素以增加它们的催化活性， 因此被认为是肾素的调节剂。可溶性PRR（sPRR）存在于 PRR的胞外结构域通过弗林蛋白酶或ADAM 19依赖性切割过程产生， 作为一种疾病生物标志物被广泛研究。虽然PRR在以下方面具有既定的作用： PRR/sPRR在低等脊椎动物和哺乳动物胚胎发生中的潜在作用， 哺乳动物肾功能和血压的调节在很大程度上仍然是难以捉摸的。内 在肾脏，PRR主要表达于远端肾单位，特别是闰细胞 收集管（CD）。在初步研究中，我们发现了一种以前从未描述过的 PRR/sPRR的旁分泌作用，其中闰细胞衍生的sPRR作用于主细胞， 刺激ENaC介导Na+重吸收。我们提出了进一步的证据，PRR/sPRR- 介导的旁分泌控制Na+转运有助于盐皮质激素盐的发病机制 高血压这项提议将检验总体假设，即在盐皮质激素过量期间， PRR/sPRR的表达在sPRR结合Frizzled-8的远端肾单位中增加， 激活β-连环蛋白信号传导，激活腺苷酸环化酶-3（AC 3）/cAMP/PKA通路， 刺激ENaC转录和活性，从而导致高血压和肾损伤。为了验证这一 假设，我们将采用条件基因打靶技术来评估的贡献， CD PRR和β-catenin与ENaC激活和高血压的关系。此外，我们将解剖sPRR- 诱导的信号传导机制涉及Frizzled-8/β-catenin的协调激活， CD细胞中的AC 3/cAMP/PKA通路。最后，我们将探索一种新的治疗潜力 盐皮质激素盐性高血压中β-连环蛋白信号传导抑制剂的研究。总的来说，这项提案 有望为高血压中肾脏PRR/sPRR的功能提供新的见解， 肾损伤

(Pro)renin receptor (PRR) binds prorenin/renin in vitro to increase their catalytic activity and therefore is postulated to be a regulator of renin. Soluble PRR (sPRR) residing in the extracellular domain of PRR is produced by furin or ADAM19-dependent cleavage process and has been widely studied as a disease biomarker. Although PRR has an established role in embryogenesis in both low vertebrates and mammals, the potential role of PRR/sPRR in regulation of mammalian renal function and blood pressure largely remains elusive. Within the kidney, PRR is predominately expressed in the distal nephron, particularly the intercalated cells of the collecting duct (CD). In preliminary studies, we discovered a previously undescribed paracrine action of PRR/sPRR with intercalated cell-derived sPRR acting on principal cells to stimulate ENaC-mediated Na+ reabsorption. We presented further evidence that PRR/sPRR- mediated paracrine control of Na+ transport contributes to pathogenesis of mineralocorticoid-salt hypertension. This proposal will test the overall hypothesis that during mineralocorticoid excess, the expression of PRR/sPRR is increased in the distal nephron where sPRR binds Frizzled-8 to activate β-catenin signaling that activates adenylyl cyclase-3 (AC3)/cAMP/PKA pathway that stimulates ENaC transcription and activity and hence hypertension and kidney injury. To test this hypothesis, we will employ conditional gene targeting techniques to evaluate the contribution of CD PRR and β-catenin to ENaC activation and hypertension. Moreover, we will dissect sPRR- induced signaling mechanisms involving coordinated activation of Frizzled-8/β-catenin and AC3/cAMP/PKA pathways in the CD cells. Lastly, we will explore a novel therapeutic potential of inhibitors of β-catenin signaling in mineralocorticoid-salt hypertension. Overall, this proposal is expected to offer novel insight into the function of renal PRR/sPRR in hypertension and kidney injury.