Fructose induced salt-sensitive hypertension: Role of thick ascending limb transport

果糖诱发的盐敏感性高血压：粗上肢运输的作用

• 批准号: 9128235
• 负责人: Pablo A. Ortiz
• 金额: $ 45.27万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-18 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128235
• 关键词: Affect; Alanine; American; Apical; Blood Pressure; Calories; Control Groups; Cyclic AMP; Dahl Hypertensive Rats; Data; Defect; Dependovirus; Development; Diabetes Mellitus; Diet; Distal; Distal convoluted renal tubule structure; Diuretics; Dominant-Negative Mutation; Epidemic; Excretory function; Fructose; Gene Deletion; Human; Hypertension; Intake; Kidney; Limb structure; Link; Mediating; Metabolic; Natriuresis; Nephrons; Obesity; Oxidative Stress; Phase; Phosphorylation; Phosphotransferases; Plasma; Population; Process; Proline; Protein Kinase; Rattus; Receptor Signaling; Renal function; Rodent; Role; Signal Transduction; Sodium Chloride; Sprague-Dawley Rats; Surface; Testing; Thick; Threonine; Urine; absorption; beta-adrenergic receptor; blood glucose regulation; blood pressure regulation; feeding; high salt diet; mutant; pressure; prevent; public health relevance; salt intake; salt sensitive hypertension; sodium-potassium chloride cotransporter 2 protein; thiazide; trafficking

 DESCRIPTION (provided by applicant): A high-fructose diet is linked to the epidemic of hypertension, diabetes, and obesity. Up to 25 million Americans consume up to 20% of their calories from added fructose1, 2. We found that feeding rats a fructose-enriched diet (20%) for 4 weeks did not increase blood pressure. However, a fructose-enriched diet combined with high salt (4% Na) caused salt-sensitive hypertension within 1 week (Figures 1, 11); prior to the development of metabolic abnormalities. The initial phase of salt-sensitive hypertension is in part mediated by a renal defect that prevents NaCl excretion during high salt intake. The thick ascending limb (TAL) reabsorbs 25% of filtered NaCl. Enhanced TAL NaCl absorption is related to salt-sensitive hypertension in humans and rodents3-5. However, the mechanism by which a fructose-enriched diet rapidly (1 week) causes salt-sensitive hypertension is not clear and the role of TAL NaCl absorption in this process is completely unknown. NaCl reabsorption by the TAL depends on the apical Na/K/2Cl cotransporter NKCC2, the target of loop diuretics. Our preliminary data show that a fructose-enriched diet enhanced NKCC2 phosphorylation at Threonine (Thr) 96,101. NKCC2 phosphorylation at Thr96, 101 activates NKCC26, 7. Our data show that NKCC2-mediated NaCl transport is abnormally elevated in rats fed fructose plus a high salt diet. However, the effects of fructose and the signaling induced in the TAL and the distal nephron have not been studied. Our data show that plasma and urine fructose increase rapidly after fructose intake. Thus, fructose reaching the nephron may be transported in by a fructose channel, activating protein kinase signaling. The only kinases known to phosphorylate Thr96, 101 of NKCC2 are SPAK (STE20/SPS1-related proline-alanine-rich kinase) and OSR1 (Oxidative Stress Responsive 1) kinases. In the TAL, these kinases specifically phosphorylate NKCC2. In the distal convoluted tubule (DCT), these kinases specifically phosphorylate the thiazide-sensitive NaCl transporter NCC. We found that a 20% fructose diet increases SPAK/OSR1 phosphorylation in TALs. In addition, stimulation of β-adrenergic receptors (β-AR) in the TAL activates NKCC213. A fructose-enriched diet may increase sympathetic activity by 2 weeks12, or enhance the sensitivity or signaling of β-AR. Our preliminary data show that β-AR stimulation increases SPAK/OSR1 phosphorylation in TALs. In the Dahl salt sensitive (SS) rat, NKCC2 and SPAK/OSR1 phosphorylation are abnormally enhanced in a normal salt diet. It is not known whether this increases the effect of fructose on blood pressure and NaCl absorption. We hypothesize that a fructose-enriched diet enhances thick ascending limb (TAL) and distal tubule (DCT) NaCl absorption by inducing NKCC2 and NCC phosphorylation via SPAK/OSR1 kinases and enhanced β-AR signaling. These effects occur within 1 week, prior to metabolic alterations, and are maintained chronically (16 weeks), promoting salt-sensitive hypertension in normal rats. In Dahl SS rats, abnormally elevated SPAK/OSR1 in the TAL, enhances the effect of fructose on blood pressure in normal- or high-salt diets.

 描述（由申请人提供）：高果糖饮食与高血压、糖尿病和肥胖症的流行有关。多达2500万美国人消耗高达20%的热量从添加果糖1，2。我们发现，给大鼠喂食富含果糖的饮食（20%）4周不会增加血压。然而，富含果糖的饮食结合高盐（4% Na）在1周内导致盐敏感性高血压（图1，11）;在代谢异常发生之前。盐敏感性高血压的初始阶段部分由肾缺陷介导，该肾缺陷在高盐摄入期间阻止NaCl排泄。厚的上升支（TAL）重吸收25%的过滤NaCl。TAL NaCl吸收增强与人类和啮齿动物的盐敏感性高血压相关3 -5。然而，富含果糖的饮食快速（1周）导致盐敏感性高血压的机制尚不清楚，TAL NaCl吸收在此过程中的作用也完全未知。TAL对NaCl的重吸收依赖于顶端Na/K/2Cl协同转运蛋白NKCC 2，这是袢利尿剂的靶点。我们的初步数据表明，富含果糖的饮食增强了NKCC 2在Thr（Thr）96，101的磷酸化。在Thr 96，101处的NKCC 2磷酸化激活NKCC 26，7。我们的数据表明，NKCC 2介导的NaCl转运在喂食果糖加高盐饮食的大鼠中异常升高。然而，果糖的作用以及TAL和远端肾单位中诱导的信号传导尚未研究。我们的数据表明，血浆和尿液果糖摄入果糖后迅速增加。因此，到达肾单位的果糖可以通过果糖通道转运，激活蛋白激酶信号传导。已知磷酸化NKCC 2的Thr 96，101的唯一激酶是SPAK（STE 20/SPS 1相关的富含脯氨酸-丙氨酸的激酶）和OSR 1（氧化应激响应1）激酶。在TAL中，这些激酶特异性磷酸化NKCC 2。在远曲小管（DCT）中，这些激酶特异性磷酸化噻嗪敏感性NaCl转运蛋白NCC。我们发现，20%的果糖饮食增加了TAL中SPAK/OSR 1的磷酸化。此外，刺激TAL中的β-肾上腺素能受体（β-AR）可激活NKCC 213。富含果糖的饮食可以增加交感神经活动2周12，或增强β-AR的敏感性或信号传导。我们的初步数据显示β-AR刺激增加TAL中SPAK/OSR 1磷酸化。在Dahl盐敏感（SS）大鼠中，NKCC 2和SPAK/OSR 1磷酸化在正常盐饮食中异常增强。目前尚不清楚这是否会增加果糖对血压和NaCl吸收的影响。我们假设富含果糖的饮食通过SPAK/OSR 1激酶诱导NKCC 2和NCC磷酸化和增强β-AR信号传导来增强粗升支（TAL）和远端小管（DCT）的NaCl吸收。这些效应发生在代谢改变之前的1周内，并长期维持（16周），促进正常大鼠的盐敏感性高血压。在Dahl SS大鼠中，TAL中SPAK/OSR 1异常升高，增强了果糖对正常或高盐饮食中血压的影响。