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

肾素（原）受体和 PPARγ 在血浆容量调节中的相互作用

• 批准号: 9729034
• 负责人: Tianxin Yang
• 金额: $ 57.55万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9729034
• 关键词: Affect; Aldosterone; Antidiabetic Drugs; Attenuated; Binding; Blood Plasma Volume; Blood Pressure; Body Fluids; Dependence; Diabetes Insipidus; Diagnosis; Disease; Duct (organ) structure; Ductal Epithelial Cell; Environment; Excretory function; Fluid Balance; Generations; Genes; Genetic Transcription; Homeostasis; Hormonal; In Vitro; Inactive Renin; Kidney; Knockout Mice; Liquid substance; Maintenance; Mediating; Medicine; Metabolic; Mutagenesis; Nephrons; Nuclear Receptors; PPAR gamma; Pathway interactions; Peptide Hydrolases; Performance; Perfusion; Play; Process; Production; Receptor Gene; Regulation; Renin; Role; Signal Transduction; Site; Sodium Chloride; Source; Testing; Thiazolidinediones; Tissues; Transcription Coactivator; Transport Process; Up-Regulation; Vasopressins; Water; base; chemical reaction; epithelial Na+ channel; in vivo; insight; novel; promoter; receptor; side effect; site-1 protease; urinary; wasting

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.

摘要 集合管（CD）是肾单位的末端部分，在微调尿液和尿液中起着关键作用。 Na+排泄以维持体液量和血压的稳态控制。这是肾单位的位置 其中转运过程受到激素因子如加压素和醛固酮的高度调节。 最近，我们和其他人发现（前）肾素受体（PRR）和过氧化物酶体增殖物激活受体γ（PPARγ）作为重要的调节因子， CD中的传输过程。在这方面，肾单位或CD中PRR的缺失诱导糖尿病 尿崩症和CD细胞中PRR的激活刺激AQP 2和/或ENaC的表达或活性。的 CD中PRR的作用部分地通过释放可溶性PRR（sPRR）来介导。另一方面，新兴 有证据表明，核受体在调节体液平衡方面发挥着重要作用， 控制这一点在CD中的PPARγ的液体保留作用中得到了强调，这是噻唑烷二酮的基础。 诱导体液潴留，这是抗糖尿病药物的主要脱靶效应。在初步研究中，我们发现 位点-1蛋白酶（S1 P）代表负责切割过程以产生 sPRR。此外，PRR和S1 P似乎是CD中PPARγ的直接靶基因。基于这些 根据观察，我们假设PPARγ转录上调CD中PRR和S1 P的表达， 导致局部sPRR产生增强和肾内RAS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)证实PPARγ是CD细胞中PRR基因的转录激活因子;（2）检测S1 P- （3）检测PRR/sPRR信号通路的依赖性 在Rosi治疗期间与原肾素/肾素结合。总的来说，这一提议产生的新信息是 有望为CD中新发现的PRR依赖性通路提供新的见解， 控制液体平衡。