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

• 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
• 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

 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）：高血压是全球“健康损失”的主要原因。多达50%的高血压是盐敏感性的，这是一种由于肾缺陷而导致的血压（BP）随饮食中的盐而升高的疾病。血管紧张素II（Ang II）是血压的关键调节剂，主要通过对肾脏（包括近端小管（PT））的作用。PT通过3型Na/H交换器（NHE 3）和Na/K ATP酶重吸收约70%的过滤Na。Ang II通过激活Ang II 1型（AT 1）受体和经典蛋白激酶C（PKC）亚型（α、β、γ）刺激转运。生理浓度的血管紧张素II，当动物是在正常的盐最大限度地刺激PT Na重吸收。当膳食盐升高时，Ang II水平下降约70%，尿钠排泄（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没有下降，盐会保留下来，血压会升高。 超过1500万美国人消耗的热量中超过20%是果糖。饮食中的果糖会导致人类高血压。我们已经证明，当大鼠消耗20%的果糖热量（20%果糖饮食）时，它们会产生盐敏感性高血压，并且血压在开始高盐饮食后1-2天开始升高。AT 1受体阻滞剂降低果糖喂养大鼠的血压;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、高盐饮食使得低浓度的Ang II能够刺激体外测量的PT转运，但不能增强最大效应。心钠素、多巴胺、一氧化氮不起作用。然而，果糖对PT的影响是否有助于果糖诱导的盐敏感性高血压及其机制尚不清楚。我们假设20%果糖饮食可减弱盐诱导的尿钠排泄，并通过激活PKCα引起盐敏感性高血压，从而使低浓度的Ang II（如高盐饮食引起的低浓度Ang II）刺激PT Na重吸收。目的1将测试20%果糖饮食是否能使高盐饮食引起的低浓度Ang II刺激NHE 3和Na/K ATP酶对PT Na的重吸收。目的2将测试20%果糖饮食是否提高基础PKCα活性，从而使低浓度的Ang II能够充分提高PKCα活性以刺激Na重吸收。目标3 将测试20%果糖饮食对PT的影响是否会降低排泄盐的能力 导致盐敏感性高血压。我们将使用最先进的技术在成像，生理学，分子生物学和基因转移。该项目将对膳食果糖如何导致盐敏感性高血压产生新的见解。