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.

美国果糖消费量的急剧增加反映了高血压发病率的增加。多于 1700 万美国人消耗的热量超过 20% 来自果糖，交叉研究直接表明 果糖会增加血压（BP）。我们报道果糖会导致盐敏感性高血压，而 葡萄糖则不然。我们还表明，膳食果糖可增强血管紧张素 II (Ang II) 近端肾单位 Na 重吸收，这是唯一能够重吸收和代谢果糖的肾单位部分。 我们在此表明​​，膳食果糖增强了 Ang II 刺激蛋白激酶 C (PKC) 活性的能力，并且 O2- 由近端肾小管产生。然而，PKC 激活和氧化应激在近端的作用 肾单位在果糖诱发的高血压中的作用尚不清楚。除了重新吸收约 70% 的过滤 钠和水，近端肾单位的主要功能之一是分泌降解过滤的蛋白酶 蛋白质，以便它们可以被重新吸收。蛋白酶诱导的上皮 Na 通道 (ENaC) 激活 集合管在多种病理状况下会导致钠潴留和高血压。迄今为止最接近的 肾小管尚未被认为是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，我们表明膳食果糖增强了两种近端肾单位的表达 蛋白酶、胰蛋白酶和 meprin β 等，并增加这些酶和尿激酶的尿液排泄。我们还展示 抑制 ENaC 可以逆转果糖引起的高血压。磷脂酶 D 和细胞内的增加 Ca (Cai) 参与许多蛋白质的分泌，并且均受到 Ang II 的刺激。因此，我们假设 膳食果糖通过增强 Ang II 诱导的 PKC 活性增加而导致盐敏感性高血压 和近端肾单位的氧化应激。这种增加的氧化应激会刺激胰蛋白酶、尿激酶和 meprin β 从该片段表达和释放。这些蛋白酶在收集过程中裂解并激活 ENaC 导管，刺激Na重吸收。目标我将测试膳食果糖是否增强 Ang II 的能力 刺激近端小管的 PKC 活性和 O2- 产生，从而有助于盐潴留和升高 在英国石油公司。目标 II 将测试膳食果糖是否增强胰蛋白酶、尿激酶和 meprin β 通过 O2-、磷脂酶 D 和 Cai 依赖性机制通过近端小管。目标 III 将测试是否 果糖诱导的胰蛋白酶、尿激酶和 meprin β 从近端小管释放，通过以下方式增强 Na 重吸收： 集合管，从而导致盐潴留和血压升高。我们将使用最先进的技术 成像、生理学、分子生物学和基因转移。该项目将对饮食如何产生新的见解 果糖引起盐敏感性高血压，目前用于治疗高血压的药物有哪些 针对集合管的 II 受体阻滞剂和利尿剂可能是最有效的。由于这些药物是 目前已批准用于此类用途，因此可以立即通过这些建议。