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:10530623
- 负责人:
- 金额:$ 63.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdoptedAmericanAngiotensin IIAngiotensin II ReceptorAngiotensin II Type 1 Receptor BlockersBlood PressureBrush BorderCaloriesCardiovascular DiseasesCellsConsumptionCross-Over StudiesDataDefectDiabetes MellitusDiseaseDiureticsDuct (organ) structureEnzymesExcretory functionFructokinasesFructoseGPI Membrane AnchorsGene TransferGlucoseHeart failureHumanHypertensionImageIncidenceKidneyKnock-outLinkLiver FailureMediatingMeprinMessenger RNAMetabolismMolecular BiologyMusNephronsNephrotic SyndromeOxidative StressPathologicPathologyPeptide HydrolasesPersonsPharmaceutical PreparationsPhospholipasePhospholipase DPhysiologyPlasmaPlayProductionProtein Kinase CProteinsRattusReactive Oxygen SpeciesRecommendationRenin-Angiotensin SystemReportingRoleSodium ChlorideSourceTechniquesTestingTissuesTrypsinUnited StatesUrokinaseWaterabsorptionblood pressure elevationdietarydietary saltdrinking waterepithelial Na+ channelglomerular filtrationhigh salt dietinhibitorinsightkidney cortexpreventrenal damagesalt sensitivesalt sensitive hypertensionsugaruptakeurinary
项目摘要
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上升反映了高血压发病率的增加。多过
1700万美国人消耗的卡路里中有20%是果糖和交叉研究直接表明的
果糖增加血压(BP)。我们报告了果糖会导致盐敏感型高血压,而
葡萄糖则不起作用。我们还发现,饮食中的果糖增强了血管紧张素II(Ang)的刺激作用
Ii)近端肾单位钠重吸收,是唯一能够重吸收和代谢果糖的肾单位。
我们在这里表明,饮食果糖增强血管紧张素转换酶II刺激蛋白激酶C(PKC)活性的能力,并
近端小管产生O2-。然而,PKC的激活和氧化应激在近端的作用
肾单位在果糖诱导的高血压中的作用还知之甚少。除了再吸收70%的过滤后的≈
钠和水,近端肾单位的主要功能之一是分泌被过滤的降解蛋白水解酶
蛋白质,这样它们就可以被重新吸收。蛋白水解酶诱导大鼠心肌上皮细胞钠通道的激活
在几种病理情况下,集合管会导致钠滞留和高血压。迄今为止的近端
小管并不被认为是尿蛋白水解酶的潜在来源。氧化应激刺激蛋白水解酶
从非肾细胞释放。在这里,我们发现饮食中的果糖增强了近端肾单位两个
这类蛋白水解酶、胰酶和meprinβ,并增加尿液中这些物质和尿激酶的排泄量。我们还展示了
抑制ENaC可逆转果糖诱导的高血压。磷脂酶D及其在细胞内的增加
CA(Cai)参与多种蛋白质的分泌,两者都受到Ang II的刺激。因此,我们假设
膳食果糖通过促进血管紧张素转换酶II诱导的PKC活性增加而导致盐敏感型高血压
以及近端肾单位的氧化应激反应。这种增加的氧化应激刺激胰酶、尿激酶和
Meprinβ在该片段中的表达和释放。这些蛋白酶在收集过程中裂解并激活ENaC
导管,刺激钠的重吸收。目的检测饮食中的果糖是否增强血管紧张素转换酶II的能力。
通过近端小管刺激PKC活性和O2-的产生,从而促进盐的滞留和升高
在英国石油公司。AIM II将测试饮食中的果糖是否促进胰酶、尿激酶和
Meprinβ通过近端小管的O2-、磷脂酶D和CaI依赖的机制。AIM III将测试
果糖诱导的近端小管胰酶、尿激酶和Meprinβ释放通过以下途径增强钠重吸收
收集管道,从而有助于英国石油公司的盐滞留和海拔升高。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方面。这个项目将对如何饮食产生新的见解
果糖会引起盐敏感型高血压,目前哪些药物用于治疗高血压,如血管紧张素转换酶
II受体阻滞剂和利尿剂靶向收集导管可能是最有效的。因为这些药物是
这些建议目前已获批准用于此类用途,但可立即予以通过。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jeffrey L. Garvin其他文献
Cross-talk between arterioles and tubules in the kidney
- DOI:
10.1007/s00467-008-0852-8 - 发表时间:
2009-01-01 - 期刊:
- 影响因子:2.600
- 作者:
YiLin Ren;Jeffrey L. Garvin;Ruisheng Liu;Oscar A. Carretero - 通讯作者:
Oscar A. Carretero
Jeffrey L. Garvin的其他文献
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{{ truncateString('Jeffrey L. Garvin', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 63.43万 - 项目类别:
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:
10117320 - 财政年份:2021
- 资助金额:
$ 63.43万 - 项目类别:
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 - 财政年份:2016
- 资助金额:
$ 63.43万 - 项目类别:
Regulation of NOS Activity in the Kidney & Hypertension
肾脏中 NOS 活性的调节
- 批准号:
8376980 - 财政年份:2012
- 资助金额:
$ 63.43万 - 项目类别:
Renal Hemodynamics: Mechanisms to Understand Disease
肾脏血流动力学:了解疾病的机制
- 批准号:
7908575 - 财政年份:2010
- 资助金额:
$ 63.43万 - 项目类别:
Regulation of NOS Activity in the Kidney & Hypertension
肾脏中 NOS 活性的调节
- 批准号:
7595338 - 财政年份:2009
- 资助金额:
$ 63.43万 - 项目类别:
Blood Pressure Regulation: Novel Roles for the Kidney
血压调节:肾脏的新作用
- 批准号:
7796788 - 财政年份:2009
- 资助金额:
$ 63.43万 - 项目类别:
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