The Role of The Proximal Nephron In Salt-Sensitive Hypertension

近端肾单位在盐敏感性高血压中的作用

基本信息

批准号：
9197670
负责人：
Jeffrey L. Garvin
金额：
$ 47.58万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197670
关键词：
Acute Affect Agonist American Angiotensin II Angiotensin-Converting Enzyme Inhibitors Animals Atrial Natriuretic Factor Blood Pressure Calories Cardiovascular Diseases Cell membrane Chronic Consumption Data Defect Diabetes Mellitus Diet Disease Dominant-Negative Mutation Dopamine Equilibrium Excretory function Fructose Gene Transfer Glucose Health Human Hypertension Image In Vitro Intake Kidney Liver Failure Losartan Measures Mediating Molecular Biology Na(+)-K(+)-Exchanging ATPase Natriuresis Nephrons Nitric Oxide Norepinephrine PRKCA gene Phlorhizin Physiological Physiology Production Protein Isoforms Protein Kinase C Rattus Receptor, Angiotensin, Type 1 Reporting Role Sodium Chloride Superoxides Techniques Testing Type 2 Angiotensin II Receptor blood pressure reduction dietary salt experimental study falls high salt diet in vivo insight prevent public health relevance receptor response salt sensitive salt sensitive hypertension sugar urinary

项目摘要

DESCRIPTION (provided by applicant): Hypertension is the leading cause of "loss of health" worldwide. As much as 50% of hypertension is salt- sensitive, a disease in which blood pressure (BP) increases with dietary salt due to a renal defect. Angiotensin II (Ang II) is a key regulator of BP primarily through actions on the kidney, including the proximal tubule (PT). The PT reabsorbs ~70% of the filtered Na via Na/H exchanger type 3 (NHE3) and Na/K ATPase. Ang II stimulates transport via activation of Ang II type 1 (AT1) receptors and classical protein kinase C (PKC) isoforms (α, β, γ). Physiological concentrations of Ang II when animals are on normal salt maximally stimulate PT Na reabsorption. When dietary salt is elevated, Ang II levels fall by ~70%, urinary Na excretion (UNaV) increases and the salt is eliminated. However, if the effects of Ang II don't decline in the face of a high-salt diet, salt is retained and BP increases. More than 15 million Americans consume >20% of their calories as fructose. Dietary fructose causes hypertension in humans. We have shown that when rats consume 20% of their calories as fructose (20% fructose diet) they develop salt-sensitive hypertension, and that BP begins to increase 1-2 days after beginning a high-salt diet. AT1 receptor blockers reduce BP in fructose-fed rats; however, the role of the PT and the mechanisms by which fructose causes salt-sensitive hypertension are unknown. We show that fructose can activate PKCα/β in isolated, perfused PTs and that a 20% fructose, high- salt diet enables low concentrations of Ang II to stimulate PT transport measured in vitro, but does not enhance the maximum effect. Atrial natriuretic factor, dopamine, nitric oxide do not play a role. However, whether the effects of fructose on the PT contribute to fructose-induced salt-sensitive hypertension and the mechanisms involved are unknown. We hypothesize that a 20% fructose diet blunts salt-induced natriuresis and causes salt-sensitive hypertension by activating PKCα thereby enabling low concentrations of Ang II such as those caused by a high-salt diet to stimulate PT Na reabsorption. Aim 1 will test whether a 20% fructose diet enables low concentrations of Ang II as caused by a high-salt diet to stimulate PT Na reabsorption by NHE3 and Na/K ATPase. Aim 2 will test whether a 20% fructose diet raises basal PKCα activity thereby enabling low concentrations of Ang II to elevate PKCα activity sufficiently to stimulate Na reabsorption. Aim 3 will test whether the effects of a 20% fructose diet on the PT reduce the ability to excrete a salt load and cause salt- sensitive hypertension. We will use state of the art techniques in imaging, physiology, molecular biology and gene transfer. This project will yield new insights into how dietary fructose causes salt-sensitive hypertension.

描述（由申请人提供）：高血压是全世界“健康损失”的主要原因，多达 50% 的高血压是盐敏感性的，这种疾病是由于肾脏缺陷而导致血压 (BP) 随饮食盐而升高。血管紧张素 II (Ang II) 是血压的关键调节剂，主要通过作用于肾脏，包括近端肾小管 (PT) 来通过 Na/H 交换器重吸收约 70% 的过滤后的 Na。 3 型 (NHE3) 和 Na/K ATP 酶通过激活 Ang II 1 型 (AT1) 受体和经典蛋白激酶 C (PKC) 亚型（α、β、γ）来刺激动物体内 Ang II 的生理浓度。正常盐最大程度地刺激 PT Na 重吸收。当饮食盐升高时，Ang II 水平下降约 70%，尿 Na 排泄 (UNaV) 增加，盐被消除。然而，如果血管紧张素II的作用在高盐饮食中不下降，盐就会被保留，血压就会升高。超过 1500 万美国人以果糖的形式消耗超过 20% 的热量膳食果糖会导致人类高血压。我们已经证明，当老鼠以果糖形式消耗 20% 的热量（20% 果糖饮食）时，它们就会患上盐敏感性高血压。开始高盐饮食 1-2 天后血压开始升高，AT1 受体阻滞剂可降低果糖喂养大鼠的血压；然而，PT 和果糖引起盐敏感性高血压的机制尚不清楚，我们发现果糖可以激活分离的灌注 PT 中的 PKCα/β，并且 20% 果糖、高盐饮食可以使低浓度的 Ang II 刺激 PT 转运。体外，但不增强心房钠尿因子，多巴胺、一氧化氮不发挥作用，但果糖是否有助于PT的作用。果糖诱发的盐敏感性高血压及其相关机制尚不清楚，我们认为 20% 果糖饮食会减弱盐诱发的尿钠排泄，并通过激活 PKCα 导致低浓度的 Ang II，例如由高浓度引起的高血压。 -盐饮食刺激 PT Na 重吸收目标 1 将测试 20% 果糖饮食是否能够像高盐饮食那样导致低浓度的 Ang II 刺激 PT Na。 NHE3 和 Na/K ATP 酶的重吸收 Aim 2 将测试 20% 果糖饮食是否会提高基础 PKCα 活性，从而使低浓度的 Ang II 足以提高 PKCα 活性以刺激 Na 重吸收。将测试 20% 果糖饮食对 PT 的影响是否会降低排盐能力我们将利用最先进的成像、生理学、分子生物学和基因转移技术，对膳食果糖如何导致盐敏感性高血压产生新的见解。