Paracrine Control of Blood Pressure by Renal Intercalated Cells

肾闰细胞对血压的旁分泌控制

• 批准号: 9070607
• 负责人: THOMAS M COFFMAN
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-19 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070607
• 关键词: Agonist; Area; Arrestins; Attenuated; Blood Pressure; Cell Line; Cell Lineage; Cells; Complex; Data; Development; Duct (organ) structure; Ductal Epithelium; Environment; Epithelial; Epithelial Cells; Excretory function; Family; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Health; Heart Diseases; Homeostasis; Hypertension; Indium; Intercalated Cell; Kidney; Kidney Diseases; Ligand Binding; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Natriuresis; Nephrons; PTGS2 gene; Pathogenesis; Pathway interactions; Physiological; Physiology; Play; Process; Production; Prostaglandins; Receptor, Angiotensin, Type 1; Regulation; Renal Blood Flow; Resistance; Risk Factors; Role; Second Messenger Systems; Severities; Signal Pathway; Signal Transduction; Site; Sodium; Sodium Chloride; Source; Stroke; Testing; Therapeutic; Tissues; Up-Regulation; Vasodilator Agents; Work; arrestin 2; base; beta-arrestin; blood pressure regulation; cyclooxygenase 2; defined contribution; insight; member; novel; novel strategies; paracrine; protein activation; receptor; response; salt balance; second messenger; urinary

 DESCRIPTION (provided by applicant): The collecting duct (CD) is the terminal segment of the nephron serving as the final determinant of sodium content in the ultrafiltrate. As such, the CD plays a key role in overall control of sodium excretion and blood pressure. CD epithelium consists of two major cell lineages, principal cells (PCs) and intercalated cells (ICs). In the traditional view, PCs are primarily responsible for sodium transport, whereas the main role of the ICs is regulating urinary acidification. However, recent studies have identified more complex functions for ICs including substantive sodium and chloride reabsorption. Here, we propose an additional role for ICs as a source of paracrine mediators inducing natriuresis and promoting resistance to hypertension. Specifically, in our preliminary studies, we discovered a pathway linked to AT1 angiotensin receptors (AT1R) in CD epithelial cells, most likely ICs, triggering expression of cyclo-oxygenase (COX)-2, generating vasodilator prostaglandins, and attenuating the development of hypertension. Along with classical second messengers linked to G-protein activation, ligand binding to GPCRs, including the AT1R, can trigger ß-arrestins to activate alternative signaling pathways with distinct physiological effects. In this regard, we find that AT1R-dependent stimulation of COX-2 in isolated medullary CDs requires ß-arrestin 2. Based on our preliminary work, we have formulated two hypotheses: (1) Expression of COX-2 and production of prostanoids by ICs is a general protective mechanism providing resistance to hypertension by preserving renal blood flow and promoting natriuresis; and (2) Activation of COX-2 by AT1R in the CD is driven by ß-arrestin signaling, independent of canonical G-protein pathways. We will test our hypotheses through the following Specific Aims: (1) Characterize the capacity of COX-2 in intercalated cells to ameliorate the severity of hypertension. (2) Define the mechanism of natriuresis triggered by AT1 receptors in intercalated cells. (3) Define the contribution of ß- arrestin to the induction of COX2 in ICs. Through these studies, we will characterize molecular control of a novel pathway linked to resistance to hypertension and attempt to uncover strategies to manipulate its activity.

 性状（由申请方提供）：集合管（CD）是肾单位的终末节段，是超滤液中钠含量的最终决定因素。因此，CD在钠排泄和血压的总体控制中起关键作用。CD上皮由两种主要细胞谱系组成，主细胞（PC）和闰细胞（IC）。在传统观点中，PC主要负责钠转运，而IC的主要作用是调节尿酸化。然而，最近的研究已经确定了IC更复杂的功能，包括实质性的钠和氯重吸收。在这里，我们提出了一个额外的作用，作为旁分泌介质的来源，诱导钠尿排泄和促进高血压的抵抗。具体而言，在我们的初步研究中，我们发现了一条与CD上皮细胞中的AT 1血管紧张素受体（AT 1 R）相关的途径，最有可能是IC，触发环加氧酶（考克斯）-2的表达，产生血管扩张剂异丙肾上腺素，并减轻高血压的发展。沿着与G蛋白活化相关的经典第二信使，配体与GPCR（包括AT 1 R）的结合可触发β-抑制蛋白以活化具有不同生理效应的替代信号传导途径。在这方面，我们发现，在孤立的髓质CD中，考克斯-2的AT 1 R依赖性刺激需要β-arrestin 2。基于我们的初步工作，我们提出了两个假设：（1）IC表达考克斯-2和产生前列腺素是一种通过保护肾血流量和促进尿钠排泄来抵抗高血压的一般保护机制;（2）CD中AT 1 R激活考克斯-2是由β-arrestin信号驱动的，不依赖于经典的G蛋白途径。我们将通过以下具体目的来验证我们的假设：（1）表征考克斯-2在闰间细胞中改善高血压严重程度的能力。(2)明确闰细胞中AT 1受体触发的钠尿排泄机制。(3)定义β- arrestin对IC中COX 2诱导的贡献。通过这些研究，我们将描述与高血压抗性相关的新途径的分子控制，并试图揭示操纵其活性的策略。