Interaction of (pro)renin receptor and PPARy in regulation of plasma volume

摘要 集合管(CD)是肾单位的终末部分，在微调尿液和尿液中起着关键作用。 钠离子排泄，维持体内液体量和血压的动态平衡控制。这就是星云地点 其中转运过程受到荷尔蒙因素的高度调节，如加压素和醛固酮。 最近，我们和其他人发现(Pro)肾素受体(PRR)和PPARγ是血管紧张素转换酶的重要调节因子 CD中的传输过程。在这方面，肾单位或CD中PRR的缺失会导致糖尿病 内陷和CD细胞内PRR的激活刺激了AQP2和/或ENaC的表达或活性。这个 CD中PRR的作用部分是通过释放可溶性PRR(SPRR)来实现的。另一方面，新兴的 有证据表明，核受体在能量以外的液体平衡调节中起着重要作用。 控制力。突显这一点的是PPARγ在CD中的保液作用，它是噻唑烷二酮的基础- 诱导液体滞留，这是抗糖尿病药物的主要非靶向作用。在初步研究中，我们发现 该位点-1蛋白水解酶(S1P)代表一种主要的蛋白水解酶，负责产生 SPRR。此外，PrR和S1P似乎都是CD中PPARγ的直接靶基因。基于这些 观察到，我们假设PPARγ在转录水平上上调CD中PRR和S1P的表达， 导致局部sPRR的产生增强和肾内RAS的激活，最终增加液体 重吸收和扩大血浆容量。为了验证这一假设，我们提出了以下三个具体目标： (1)将PPARγ定义为CD细胞中PrR基因的转录激活因子；(2)检测S1P-1的作用。 衍生的sPRR在介导Rosi诱导的液体滞留中的作用，(3)检测PRR/sPRR信号的依赖性 ROSI治疗中与肾素原/肾素结合的研究。总而言之，这项提案产生的新信息是 有望为CD中新发现的内分泌平衡依赖PRR途径提供新的见解 流体平衡的控制。

Abstract The collecting duct (CD), the terminal part of the nephron, plays a pivotal role in fine-tuning urinary water and Na+ excretion to maintain homeostatic control of body fluid volume and blood pressure. This is the nephron site where the transport processes are highly regulated by hormonal factors such as vasopressin and aldosterone. Recently, we and others have discovered (pro)renin receptor (PRR) and PPARγ as important regulators of the transport processes in the CD. In this regard, deletion of PRR in the nephron or the CD induces diabetes insipidus and activation of PRR in the CD cells stimulates expression or activity of AQP2 and/or ENaC. The action of PRR in the CD is mediated in part by releasing soluble PRR (sPRR). On the other hand, emerging evidence shows that nuclear receptors play an important role in regulation of fluid balance beyond the energy control. This is highlighted by the fluid-retaining action of PPARγ in the CD, which underlies thiazolidinedione- induced fluid retention, a major off-target effect of the antidiabetic agents. In preliminary studies, we discovered that site-1 protease (S1P) represents a predominant protease responsible for the cleavage process to produce sPRR. Moreover, both PRR and S1P appear to be direct target genes of PPARγ in the CD. Based on these observations, we hypothesize that PPARγ transcriptionally upregulates expression of PRR and S1P in the CD, leading to enhancement of local sPRR production and activation of intrarenal RAS, ultimately increasing fluid reabsorption and expanding plasma volume. To test this hypothesis, we propose the following 3 specific aims: (1) to define PPARγ as a transcriptional activator of PRR gene in the CD cells, (2) to test the role of S1P- derived sPRR in mediating Rosi-induced fluid retention, (3) to test the dependence of PRR/sPRR signaling on binding to prorenin/renin during Rosi treatment. Together, new information resulted from this proposal is expected to offer new insight into the newly discovered PRR-dependent pathway in the CD for homeostatic control of fluid balance.