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）： 肾内肾素-血管紧张素系统（RAS）与生理条件下和高血压情况下的血压（BP）控制有关。该系统的一个组成部分，集合管 (CD) 衍生的肾素/肾素原，近年来已成为越来越多研究的主题。 CD 产生的肾素于 1999 年得到明确鉴定，并推测其会水解肾小管液体血管紧张素原 (AGT)，最终导致管腔内血管紧张素 II (AngII) 的产生。由于管腔 AngII 可以刺激 CD Na 转运，因此人们认为 CD 衍生的肾素在控制 Na 重吸收和血压方面发挥了作用。随后的研究确定，CD 衍生的肾素产生的调节方式与肾小球旁装​​置 (JGA) 衍生的肾素不同。特别是，AngII 增加 CD 细胞释放肾素，同时抑制 JGA 分泌肾素。这表明 CD 肾素可能导致 AngII 诱导的高血压。 2009年，CD细胞被描述为表达管腔肾素原受体（PRR）；由于肾素或肾素原与 PRR 的结合可以增强 AGT 催化并激活细胞内信号传导途径，因此进一步支持了以下观点：系统 存在其中CD衍生的肾素和/或肾素原调节CD功能以最终影响血压。尽管在了解 CD 肾素/肾素原的生物学作用方面投入了大量精力，但迄今为止还没有研究真正确定 CD 衍生的肾素/肾素原是否能够并且确实控制 Na 重吸收和血压。为了解决这个根本性的重要问题，我们的实验室开发了在 CD 内选择性过度表达或删除肾素/肾素原的小鼠模型。我们的初步研究结果表明，CD 衍生的肾素/肾素原可调节血压，并且这种作用在正常生理条件下是明显的。这些令人兴奋的数据构成了当前提案的基础，其中我们将首次分析 CD 肾素/肾素原在控制血压和肾功能中的生理和病理生理相关性。该提议的主要假设是： 1) CD 衍生的肾素/肾素原，通过刺激管腔 AngII 形成和/或直接影响 PRR，通过特定通道增加 CD Na 和水的重吸收并升高血压； 2）CD衍生的肾素/肾素原有助于高外源性或内源性AngII诱导的高血压； 3) CD 肾素/肾素原的产生由 AngII 通过特定的腺苷酸环化酶 (AC) 同工型、G 蛋白、Ca2+ 信号通路和蛋白激酶 C (PKC) 进行调节。该提案有三个具体目标。目标 1 将使用 CD 中肾素/肾素原过度表达或缺失的小鼠来确定 CD 衍生的肾素/肾素原对血压和肾功能的影响。 CD 肾素/肾素原增加或缺失的影响将根据血压、尿钠和水排泄以及相关受影响的通道、循环激素和肾内 RAS 进行评估。目标 2 将确定 CD 衍生的肾素/肾素原在与过量 AngII 相关的高血压中的作用。将评估 CD 肾素/肾素原缺乏对由于外源性（输注）或内源性（肾动脉狭窄）AngII 增加而导致的高血压的影响。目标 3 将确定 CD 肾素/肾素原在基础和 AngII 刺激条件下如何受到调节。使用具有 CD 特异性删除 AC 亚型的新型小鼠系、细胞系和原代培养物，将检查特定 AC 亚型、G 蛋白和 Ca 信号通路在调节 CD 肾素/肾素原产生中的参与情况。