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

肾素（原）受体在肾脏醛固酮信号传导中的作用

• 批准号: 9921471
• 负责人: Tianxin Yang
• 金额: $ 52.84万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921471
• 关键词: Adenylate Cyclase; Adult; Aldosterone; Antihypertensive Agents; Attenuated; Binding; Biological Markers; Blood Pressure; CREB1 gene; Cells; Collecting Cell; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DOCA; Disease; Distal; Duct (organ) structure; Ductal Epithelial Cell; Embryonic Development; Extracellular Domain; Gene Targeting; Genetic Transcription; Hypertension; In Vitro; Inactive Renin; Injury to Kidney; Intercalated Cell; Kidney; Mammals; Mediating; Mineralocorticoids; Nephrons; Pathogenesis; Pathway interactions; Process; Regulation; Renal function; Renin; Role; Signal Transduction; Sodium Chloride; Techniques; Testing; United States; Vertebrates; beta catenin; blood pressure regulation; epithelial Na+ channel; inhibitor/antagonist; insight; novel; novel therapeutics; paracrine; receptor; receptor binding; salt sensitive hypertension

(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.

（Pro）肾素受体（PRR）在体外结合原肾素/肾素，提高它们的催化活性