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: 10321298
• 负责人: Jeffrey L. Garvin
• 金额: $ 63.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321298
• 关键词: Adopted; American; Angiotensin II; Angiotensin II Receptor; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calories; Cardiovascular Diseases; Consumption; Cross-Over Studies; Data; Diabetes Mellitus; Disease; Diuretics; Duct (organ) structure; Enzymes; Excretory function; Fructokinases; Fructose; GPI Membrane Anchors; Gene Transfer; Glucose; Heart; Hypertension; Image; Incidence; Kidney; Knock-out; Link; Liver Failure; Mediating; Meprin; Messenger RNA; Molecular Biology; Mus; Nephrons; Oxidative Stress; Pathologic; Pathology; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phospholipase; Phospholipase D; Physiology; Plasma; Play; Production; Protein Kinase C; Proteins; Rattus; Reactive Oxygen Species; Recommendation; Renin-Angiotensin System; Reporting; Role; Sodium Chloride; Source; Techniques; Testing; Tissues; Trypsin; United States; Urokinase; Water; blood pressure elevation; dietary; dietary salt; drinking water; epithelial Na+ channel; glomerular filtration; high salt diet; inhibitor; insight; prevent; renal damage; salt sensitive; salt sensitive hypertension; sugar; uptake; urinary

The dramatic rise in U.S. fructose consumption mirrors the increase in the incidence of hypertension. More than 17 million Americans consume >20% of their calories as fructose and crossover studies directly show that fructose increases blood pressure (BP). We reported that fructose causes salt-sensitive hypertension while glucose does not. We also showed that dietary fructose enhances the stimulatory effect of angiotensin II (Ang II) on proximal nephron Na reabsorption, the only nephron segment able to reabsorb and metabolize fructose. We show here that dietary fructose enhances the ability of Ang II to stimulate protein kinase C (PKC) activity and O2- production by proximal tubules. However, the roles of PKC activation and oxidative stress in the proximal nephron in fructose-induced hypertension are poorly understood. In addition to reabsorbing ≈70% of the filtered Na and water, one of the primary functions of the proximal nephron is to secrete proteases that degrade filtered proteins so they can be reabsorbed. Protease-induced activation of the epithelial Na channel (ENaC) in the collecting duct causes Na retention and hypertension in several pathological conditions. Heretofore proximal tubules have not been thought of as a potential source for urinary proteases. Oxidative stress stimulates protease release from non-renal cells. Here we show that dietary fructose enhances proximal nephron expression of two such proteases, trypsin and meprin β, and augments the urinary excretion of these and urokinase. We also show that inhibition of ENaC reverses fructose-induced hypertension. Phospholipase D and increases in intracellular Ca (Cai) are involved in the secretion of many proteins, and both are stimulated by Ang II. Thus, we hypothesize that dietary fructose causes salt-sensitive hypertension by enhancing Ang II-induced increases in PKC activity and oxidative stress in the proximal nephron. This increased oxidative stress stimulates trypsin, urokinase and meprin β expression and release from this segment. These proteases cleave and activate ENaC in collecting ducts, stimulating Na reabsorption. Aim I will test whether dietary fructose enhances the ability of Ang II to stimulate PKC activity and O2- production by proximal tubules thereby contributing to salt retention and elevations in BP. Aim II will test whether dietary fructose enhances the expression and release of trypsin, urokinase and meprin β by proximal tubules via O2-, phospholipase D and Cai-dependent mechanisms. Aim III will test whether fructose-induced trypsin, urokinase and meprin β release from proximal tubules augments Na reabsorption by collecting ducts, thereby contributing to salt retention and elevations in BP. 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, and which drugs currently used to treat hypertension such as Ang II receptor blockers and diuretics targeting collecting ducts will likely be most efficacious. Since these drugs are currently approved for such use, the recommendations could be adopted immediately.

美国果糖消耗的急剧上升反映了高血压发病率的增加。多于 作为果糖和跨界研究，有1700万美国人消耗> 20％的卡路里，直接表明 果糖会增加血压（BP）。我们报道果糖会引起盐敏感的高血压，而 葡萄糖没有。我们还表明，饮食果糖增强了血管紧张素II的刺激作用（ANG ii）在近端肾脏Na的重吸收上，唯一可以重新吸收和代谢果糖的肾单位段。 我们在这里表明饮食果糖增强了ANG II刺激蛋白激酶C（PKC）活性的能力和 O2-近端管产生。但是，PKC激活和氧化应激在近端的作用 果糖诱导的高血压中的肾单位了解较少。除了重新吸收约70％的过滤 Na和Water，近端肾单位的主要功能之一是将降解过滤的秘密蛋白酶 蛋白酶诱导的上皮Na通道（ENAC）激活 在几种病理条件下，收集管道会导致NA保留和高血压。迄今为止 尚未将其视为尿蛋白酶的潜在来源。氧化应激刺激蛋白酶 从非肾细胞释放。在这里，我们表明饮食果糖增强了两个 这些蛋白酶，胰蛋白酶和meprinβ，并增强了这些蛋白酶和尿激酶的尿排泄。我们也显示 抑制ENAC会逆转果糖诱导的高血压。磷脂酶D并在细胞内增加 Ca（CAI）参与了许多蛋白质的分泌，并且两者都受到ANG II的刺激。那我们假设 饮食果糖通过增强ANG II诱导的PKC活性增加而引起盐敏感的高血压 和近端肾单位中的氧化应激。增加氧化应激会刺激胰蛋白酶，尿激酶和 meprinβ表达并从该部分释放。这些蛋白酶清除并激活ENAC收集 管道，刺激Na的重吸收。目的我将测试饮食果糖是否增强了ANG II的能力 刺激PKC活性和O2-通过近端管的产生，从而有助于盐保留和高程 在BP中。 AIM II将测试饮食果糖是否增强了胰蛋白酶，尿蛋白酶和 MEPRINβ通过O2-，磷脂酶D和CAI依赖性机制通过近端小管。 AIM III将测试是否 果糖诱导的胰蛋白酶，尿蛋白酶和MEPRINβ从代理块茎中释放，从 收集管道，从而有助于盐和BP的升高。我们将使用最先进的技术 在成像，生理，分子生物学和基因转移中。该项目将对饮食的方式产生新的见解 果糖会引起盐敏感的高血压，哪些药物目前用于治疗高血压，例如ANG II接收器阻滞剂和靶向收集管道的利尿剂可能是最有效的。由于这些药物是 目前已批准使用该建议，可以立即通过。