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.

 描述（由适用提供）：收集导管（CD）是肾单位的末端段，作为超滤中钠含量的最终确定剂。因此，CD在钠极端和血压的总体控制中起着关键作用。 CD上皮由两个主要的细胞谱系，主要细胞（PC）和插入细胞（ICS）组成。从传统观点看，PC是主要负责钠运输的主要负责，而IC的主要作用是调节尿酸化。但是，最近的研究已经确定了包括实质性钠和氯化物重吸收在内的IC的更复杂的功能。在这里，我们提出了ICS作为旁分泌介质的来源的额外作用，该旁分泌介质引起了纳地尿和促进对高血压的抗性。具体而言，在我们的初步研究中，我们发现了与CD上皮细胞中AT1血管紧张素受体（AT1R）相关的途径，最有可能的ICS触发了环氧酶（COX）-2的表达，生成血管静脉炎剂Prostaglandins，并降低了高血压的发育。除了与G蛋白激活相关的经典第二信使外，配体与GPCR（包括AT1R）的结合可以触发β-arrestin，以激活具有不同物理效应的替代信号通路。在这方面，我们发现在孤立的髓质CD中对Cox-2的AT1R依赖性刺激需要β-arrestin 2。根据我们的初步工作，我们提出了两个假设：（1）COX-2的表达和ICS产生的ICS产生ICS是一种通过肾脏流动的一般保护机制，可抗肾血液流动，并促进NATRI，并促进NATRI natri natri， （2）CD中AT1R激活COX-2是由β-arrestin信号传导驱动的，这与规范的G蛋白途径无关。我们将通过以下内容检验我们的假设。具体目的：（1）表征COX-2在插入细胞中改善高血压严重程度的能力。 （2）定义了插入细胞中AT1受体触发的Natriuresis的机理。 （3）定义ß-停滞蛋白对IC中Cox2诱导的贡献。通过这些研究，我们将表征与与高血压抗性有关的新途径的分子控制，并试图发现操纵其活性的策略。