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

(Pro)肾素受体(PRR)在体外与前肾素/肾素结合以增加其催化活性，并 因此被认为是肾素的调节者。可溶性PRR(SPRR)驻留在 PRR的胞外区是通过依赖Furin或ADAM19的切割过程产生的，并且 作为一种疾病生物标志物已被广泛研究。尽管PRR在以下方面具有既定的作用 在低等脊椎动物和哺乳动物中，PrR/sPRR在胚胎发生中的潜在作用 哺乳动物的肾功能和血压的调节在很大程度上仍然难以捉摸。在 肾，PRR主要表达于远端肾单位，尤其是间质细胞。 收集管道(CD)。在初步研究中，我们发现了一种以前没有描述过的 PRR/sPRR与嵌入细胞来源的sPRR作用于主细胞的旁分泌作用 刺激ENaC介导的Na+重吸收。我们提出了进一步的证据，证明PRR/sPRR- 钠离子转运的旁分泌调控参与糖皮质激素盐的发病 高血压。这一提议将检验总体假设，即在矿质皮质激素过量期间， PrR/sPRR在远端肾单位的表达增加，sPRR与Frizzled8结合 激活β-连环蛋白信号，激活腺酰环化酶-3(Ac3)/cAMP/PKA途径，从而 刺激ENaC转录和活性，从而导致高血压和肾脏损伤。为了测试这一点 假设，我们将使用条件基因打靶技术来评估 CDPRR和β-连环蛋白与ENaC激活和高血压的关系。此外，我们还将剖析sprr- 涉及Frizzled8/β-catenin协同激活的诱导信号机制 CD细胞中的AC3/cAMP/PKA通路。最后，我们将探索一种新的治疗潜力 盐皮质激素性高血压患者β-连环蛋白信号抑制物的研究。总体而言，这项建议 有望为肾脏PRR/sPRR在高血压和高血压中的作用提供新的见解。 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.