Collecting duct renin regulation of blood pressure in health and hypertension

集合管肾素对健康和高血压患者血压的调节作用

• 批准号: 8993858
• 负责人: Donald E Kohan
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993858
• 关键词: Address; Adenylate Cyclase; Affect; Angiotensin II; Angiotensinogen; Binding; Blood Pressure; Catalysis; Cell Line; Cells; Data; Diabetes Mellitus; Diet; Duct (organ) structure; Excretory function; GTP-Binding Proteins; Health; Hormones; Hypertension; Inactive Renin; Infusion procedures; Intercalated Cell; Juxtaglomerular Apparatus; Kidney; Kininogenase; Knock-out; Laboratories; Lead; Liquid substance; Messenger RNA; Modeling; Mus; Natriuretic Peptides; Peptide Receptor; Physiological; Play; Population; Production; Protein Isoforms; Protein Kinase C; Regulation; Regulatory Pathway; Renal Artery Stenosis; Renal function; Renin; Renin-Angiotensin System; Research Design; Role; Signal Pathway; Sodium; System; Time; Veterans; Water; base; blood pressure regulation; insight; mouse model; novel; overexpression; prorenin receptor; protein expression; public health relevance; receptor expression; response; urinary; water channel

DESCRIPTION (provided by applicant): The intrarenal renin-angiotensin system (RAS) has been implicated in control of blood pressure (BP) under physiologic conditions and in the setting of hypertension. One component of this system, collecting duct (CD)- derived renin/prorenin, has been the subject of increasing studies in recent years. Renin production by the CD was definitively identified in 1999 and was hypothesized to hydrolyze tubule fluid angiotensinogen (AGT), ultimately leading to production of intraluminal angiotensin II (AngII). Since luminal AngII can stimulate CD Na transport, the idea developed that CD-derived renin played a role in controlling Na reabsorption and BP. Ensuing studies determined that CD-derived renin production was regulated differently than juxtaglomerular apparatus (JGA)-derived renin; in particular, AngII increased renin release by CD cells, while inhibiting renin secretion by the JGA. This suggested that CD renin might contribute to AngII-induced hypertension. In 2009, CD cells were described to express luminal prorenin receptors (PRR); since binding of renin or prorenin to PRR can increase AGT catalysis and activate intracellular signaling pathways, further support was lent to the notion that a system existed wherein CD-derived renin and/or prorenin modulated CD function to ultimately affect BP. Despite the substantial effort invested in understanding the biologic role of CD renin/prorenin, no studies to date have actually determined if CD-derived renin/prorenin can and does control Na reabsorption and BP. To address this fundamentally important question, our laboratory has developed mouse models that overexpress or delete renin/prorenin selectively within the CD. Our preliminary findings indicate that CD- derived renin/prorenin regulates BP and that this effect is evident under normal physiological conditions. These exciting data form the basis for the current proposal wherein we will analyze, for the first time, the physiological and pathophysiological relevance of CD renin/prorenin in the control of BP and renal function. The major hypotheses of this proposal are: 1) CD-derived renin/prorenin, via stimulation of luminal AngII formation and/or direct effects on the PRR, increases CD Na and water reabsorption via specific channels and raises BP; 2) CD-derived renin/prorenin contributes to the hypertension induced by high exogenous or endogenous AngII; and 3) CD renin/prorenin production is regulated by AngII via specific adenylyl cyclase (AC) isoforms, G proteins, Ca2+ signaling pathways, and protein kinase C (PKC). The proposal has three specific aims. Aim 1 will determine the effect of CD-derived renin/prorenin on blood pressure and renal function using mice with overexpressed or absent renin/prorenin in the CD. The impact of increased or absent CD renin/prorenin will be assessed with regard to BP, urinary Na and water excretion and the relevant affected channels, circulating hormones and the intrarenal RAS. Aim 2 will determine the role of CD-derived renin/prorenin in hypertension associated with excess AngII. The effect of CD renin/prorenin deficiency on hypertension due to increased exogenous (infused) or endogenous (renal artery stenosis) AngII will be assessed. Aim 3 will determine how CD renin/prorenin is regulated under basal and AngII-stimulated conditions. Using novel mouse lines with CD- specific deletion of AC isoforms, cells lines and primary cultures, the involvement of specific AC isoforms, G proteins and Ca signaling pathways in regulating CD renin/prorenin production will be examined.

描述（由申请人提供）： 在生理条件和高血压的情况下，培养肾上素 - 血管紧张素系统（RAS）与血压（BP）有关。近年来，该系统的一个组成部分是收集导管（CD）的肾素/prorenin，这是越来越多的研究的主题。 CD生产肾素​​在1999年被确定，并被认为水解小管流体血管紧张素原（AGT），最终导致了腔内血管紧张素II（ANGII）的产生。由于Luminal Angii可以刺激CD NA的运输，因此提出了CD衍生的肾素在控制Na重吸收和BP中发挥作用的想法。随之而来的研究确定，CD衍生的肾素的产生与近局体的肾素（JGA）衍生的肾素的调节不同。特别是，ANGII增加了CD细胞释放的肾素释放，同时抑制JGA的肾素分泌。这表明CD肾素可能有助于血管诱导的高血压。在2009年，CD细胞被描述为表达腔肾上腺素受体（PRR）。由于肾素或prorenin与PRR的结合可以增加AGT催化并激活细胞内信号通路，因此进一步支持了系统 存在于其中CD衍生的肾素和/或prorenin调节CD功能以最终影响BP的情况。尽管在理解CD肾素/prorenin的生物学作用方面做出了巨大的努力，但迄今为止，尚无研究确定CD衍生的肾素/prorenin是否可以并且确实可以控制NA的重吸收和BP。为了解决这个根本重要的问题，我们的实验室开发了在CD中选择性地删除肾素/prorenin的小鼠模型。我们的初步发现表明，CD衍生的肾素/prorenin调节BP，并且在正常生理条件下这种作用是明显的。这些令人兴奋的数据构成了当前建议的基础，其中我们将首次分析Cd肾素/prorenin在BP和肾功能中的生理和病理生理学相关性。该提案的主要假设是：1）CD衍生的肾素/prorenin，通过刺激腔内血管形成和/或直接对PRR的影响，通过特定的通道增加CD NA并增加了水的吸收，并提高了BP； 2）CD衍生的肾素/prorenin有助于由高外源性或内源性ANGII引起的高血压； 3）CD肾素/prorenin的产生由ANGII通过特定的腺苷酸环化酶（AC）同工型，G蛋白，Ca2+信号传导途径和蛋白激酶C（PKC）调节。该提案具有三个具体目标。 AIM 1将使用CD中具有过表达或不存在的肾素/prorenin的小鼠来确定CD衍生的肾素/prorenin对血压和肾功能的影响。将评估增加或不存在CD肾素/prorenin的影响，以尿尿和水分排泄以及相关影响的通道，循环激素和肾内RAS评估。 AIM 2将确定CD衍生的肾素/prorenin在与过量ANGII相关的高血压中的作用。将评估CD肾素/prorenin缺乏症对增加外源性（注入）或内源性（肾动脉狭窄）ANGII引起的高血压的影响。 AIM 3将确定如何在基础和Angii刺激的条件下调节CD肾素/prorenin。使用具有AC同工型，细胞系和原代培养物的CD特异性缺失的新型小鼠系，将检查特定的AC同工型，G蛋白和Ca信号传导途径的参与，以调节CD肾素/prorenin的产生。