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（适用提供）：高血压是全球“健康丧失”的主要原因。多达50％的高血压是盐敏感的，一种由于肾脏缺陷而随着饮食盐而增加的疾病。血管紧张素II（ANG II）是通过肾脏（包括近端管（PT））作用的BP主要调节剂。 PT通过Na/H交换器3型（NHE3）和Na/K ATPase重新吸收了约70％的NA/H换热器。 ANG II通过ANG II类型1（AT1）受体和经典蛋白激酶C（PKC）同工型（α，β，γ）的激活刺激转运。当动物处于正常盐上时，ANG II的生理浓度会刺激Pt Na的吸收。当饮食盐升高时，ANG II的水平下降了约70％，尿Na排泄（UNAV）增加并消除了盐。但是，如果面对高盐饮食时Ang II的影响不会下降，则保留盐并增加BP。超过1500万美国人将其卡路里的卡路里占果糖的20％。饮食果糖会导致人类高血压。我们已经表明，当大鼠将20％的卡路里作为果糖（20％果糖饮食）消耗时，他们会产生盐敏感性的高血压，并且在开始高盐饮食后，BP开始增加1-2天。 AT1受体阻滞剂减少了果糖喂养大鼠的BP；然而，PT的作用和果糖引起盐敏感性高血压的机制尚不清楚。我们表明，果糖可以在分离的，灌注的PT中激活PKCα/β，并且20％的果糖高盐饮食使低浓度的ANG II可以刺激体外测量的PT转运，但不会增强最大作用。心房亚钠因子，多巴胺，一氧化氮不起作用。但是，果糖对PT的影响是否有助于果糖诱导的盐敏感性高血压和所涉及的机制。我们假设20％的果糖饮食钝化了盐诱导的硝酸盐，并通过激活PKCα引起盐敏感的高血压，从而使低浓度的ANG II（例如由高盐饮食引起的）刺激PT NA的吸收。 AIM 1将测试20％的果糖饮食是否可以使高盐饮食引起的低浓度ANG II刺激NHE3和Na/K ATPase刺激PT NA的吸收。 AIM 2将测试20％的果糖饮食是否会提高碱性PKCα活性，从而使低浓度的ANG II能够充分升高PKCα活性以刺激NA的重吸收。目标3 将测试20％果糖饮食对PT的影响是否会降低准确盐的能力负载并引起对盐敏感的高血压。我们将在成像，生理，分子生物学和基因转移中使用最先进的技术。该项目将对饮食果糖如何引起盐敏感性高血压产生新的见解。