Integrated control of collecting duct function and endothelin synthesis

集合管功能和内皮素合成的综合控制

• 批准号: 9003362
• 负责人: Donald E Kohan
• 金额: $ 10.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003362
• 关键词: Address; Affect; Animals; Area; Blood Pressure; Body Fluids; Cells; Cilia; Clinical Trials; Diuresis; Diuretics; Duct (organ) structure; Endothelin; Endothelin-1; Excretory function; Figs - dietary; Homeostasis; Human; Investigation; Kidney; Knock-out; Link; Liquid substance; Mediating; Messenger RNA; Modeling; Natriuresis; Nitric Oxide; Nitric Oxide Synthase; Oxides; PKD2 protein; Pathway interactions; Physiological; Play; Process; Production; Protein Isoforms; Purinergic P2 Receptors; Purinoceptor; Rat-1; Regulation; Renal function; Research Design; Role; Signal Transduction; Sodium Chloride; System; Testing; Water; Water consumption; autocrine; base; blood pressure regulation; cell type; fluid flow; novel; polycystic kidney disease 1 protein; public health relevance; receptor; response; salt intake; salt sensitive hypertension; saluretic; success; urinary

 DESCRIPTION (provided by applicant): The collecting duct (CD) endothelin-1 (ET-1) system plays a key role in regulating blood pressure (BP) and urinary Na+ excretion. ET-1 directly inhibits CD Na+ and water reabsorption; CD-specific knockout of ET-1 causes salt-sensitive hypertension. ET receptor antagonist-induced fluid retention, a major factor limiting the success of these agents in clinical trials, is largely due to blockade of CD ET-1 actions. Given that CD ET-1 modulates body fluid volume (BFV) homeostasis, it is important to define how this system is regulated by changes in BFV status. Urinary ET-1 excretion is increased in response to salt or water loading; since urinary ET-1 largely derives from the CD, these findings suggest that BFV regulates CD ET-1 production. The mechanism(s) by which BFV expansion enhances CD ET-1 synthesis are incompletely understood. We have found that flow enhances ET-1 production by the inner medullary CD (IMCD) through activation of Ca2+- depending signaling and may require primary cilia and polycystins-1 and -2; these findings raise exciting possibilities about te role of primary cilia and polycystins in the regulation of CD ET-1 and CD salt and water reabsorption. In addition, we found that the purinergic receptors P2Y2 and P2X7 may be important in the IMCD ET-1 flow response, suggesting a link between acutely (ATP) and chronically (ET-1) acting natriuretic and diuretic factors in the CD. We have also found that nitri oxide (NO), likely via NO synthase 3, is necessary for flow stimulation of IMCD ET-1; since NO has never been shown to increase ET-1, this represents a novel and important area of investigation. Taken together, these new findings form the basis for our key hypotheses: 1) Flow increases IMCD ET-1 production through an interplay between cilia, polycystins-1 and -2, P2Y2 and P2X7 receptors, NO and Ca2+-depending signaling; and 2) Cilia, polycystins-1 and -2, P2Y2 and P2X7 receptors, and NO modulation of CD ET-1 affects CD salt and water handling and BP. The following specific aims will be addressed: 1) Evaluate cilia and polycystin regulation of CD ET-1 synthesis and renal function. This involves determining if cilia and polycystins-1 and -2 in the CD regulate BP and salt and water excretion under physiological conditions, if ET-1 plays a role in such regulation, and how cilia and polycystins-1 and -2 in the CD modulate ET-1 production. 2) Evaluate purinergic regulation of CD ET-1 synthesis and renal function. This involves determining if P2Y2 and P2X7 modulate BP and urinary salt and water excretion under physiological conditions, if CD ET-1 plays a role in such regulation, and how P2Y2 and P2X7 in the CD modulate ET-1 production. 3) Evaluate NO regulation CD ET-1 synthesis and renal function. This involves identification of the role of specific NOS isoforms in the CD in modulating BP and urinary salt and water excretion under physiological conditions, if CD ET-1 plays a role in such regulation, and how NOS isoforms in the CD modulate ET-1 production. Taken together, this studies will greatly enhance understanding of how tubule fluid flow regulates CD salt and water reabsorption and the role of ET-1 in this process.

 描述（由适用提供）：收集导管（CD）内皮素-1（ET-1）系统在控制血压（BP）和尿Na+ Extreme中起关键作用。 ET-1直接抑制CD Na+和水的吸收； ET-1的CD特异性敲除导致盐敏感性高血压。 ET受体拮抗剂诱导的液保留率是限制这些药物在临床试验中成功的主要因素，这主要是由于阻断了CD ET-1作用。鉴于CD ET-1调节体液体积（BFV）稳态，因此必须定义该系统如何受BFV状态的变化调节很重要。尿液ET-1的排泄因盐或水的负荷而增加；由于尿液ET-1很大程度上源自CD，因此这些发现表明BFV调节CD ET-1的产生。 BFV扩展增强CD ET-1合成的机制尚不完全理解。我们发现，流动通过CA2+的激活取决于信号传导来增强内髓CD（IMCD）的产生，并且可能需要原代纤毛和polycystins-1和-2。这些发现引发了关于原发性纤毛和多囊这在CD ET-1和CD盐和水的调节中的作用的令人兴奋的可能性。此外，我们发现嘌呤能受体P2Y2和P2X7在IMCD ET-1流动响应中可能很重要，这表明CD中急性（ATP）与慢性（ET-1）作用敏感（ET-1）之间存在联系。我们还发现，氧化硝基（NO）可能是通过合酶3进行的，对于IMCD ET-1的流动刺激是必需的。由于从未证明没有增加ET-1，因此这代表了一个新颖而重要的投资领域。综上所述，这些新发现构成了我们关键假设的基础：1）通过纤毛，polycystins-1和-2，p2y2和p2x7受体之间的相互作用，流动增加了IMCD ET-1的产生，NO和Ca2+depeperdenditigned信号传导； 2）纤毛，polycystins-1和-2，P2Y2和P2X7受体，CD ET-1的调节不影响CD盐和水的处理和BP。将解决以下具体目的：1）评估CDET-1合成和肾功能的纤毛和多囊蛋白调节。这涉及确定CD中的纤毛和polycystins-1和-2是否在ET-1在这种调节中起作用，以及CD中CILIA和Polycystins-1和-2在CD中如何调节ET-1的产生，是否扮演BP，盐和水极端条件。 2）评估CD ET-1合成和肾功能的嘌呤能调节。这涉及确定P2Y2和P2X7是否调节BP以及尿盐和水的极端物理条件，CD ET-1是否在此调节中起作用，以及CD中的P2Y2和P2X7如何调节ET-1的产生。 3）否评估CD ET-1的合成和肾功能。如果CD ET-1在此调节中起作用，以及CD中的NOS同工型如何调节ET-1的产生，则这涉及鉴定特定的NOS同工型在调节BP和尿液和水极端条件中的作用。综上所述，这项研究将大大增强对小管流体流动如何调节CD盐和水的吸收以及ET-1在此过程中的作用的理解。