Impact of Dietary Fructose and High Salt Diet on Neurocardiovascular and Renal Function

膳食果糖和高盐饮食对神经心血管和肾功能的影响

• 批准号: 10456416
• 负责人: Noreen F Rossi
• 金额: $ 64.1万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456416
• 关键词: Ablation; Acute; Adult; Aging; Angiotensins; Animals; Attention; Baroreflex; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chronic; Chronic Kidney Failure; Clinical Research; Conscious; Consumption; DOCA; Data; Deafferentation procedure; Denervation; Development; Diet; Diet Habits; Disease; Early Diagnosis; Early identification; Endothelium; Event; Exercise; Fluorescein-5-isothiocyanate; Fructose; Glomerular Filtration Rate; Goals; Heart; Heart Diseases; Heart failure; Human; Hypertension; Impairment; Individual; Ingestion; Insulin Resistance; Intake; Interruption; Intervention; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Laboratories; Measurable; Measurement; Modeling; Morbidity - disease rate; Motivation; Musculoskeletal; Myocardial; Myocardial Infarction; Myography; Nerve; Oxidative Stress; Pain; Pharmacology; Pharmacotherapy; Physiologic pulse; Physiological; Population; Positioning Attribute; Pre-Clinical Model; Prediabetes syndrome; Principal Investigator; Publishing; Pulse Pressure; Rattus; Renal Blood Flow; Renal function; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Rodent Model; Societies; Sodium; Sodium Chloride; Sprague-Dawley Rats; Stroke; Subfornical Organ; Sympathectomy; Sympatholytics; Symptoms; Systolic heart failure; TNFRSF1A gene; Technology; Testing; Therapeutic Intervention; Time; Translating; Ultrasonography; arterial stiffness; attributable mortality; blood pressure elevation; cardiometabolism; cardiovascular risk factor; clinical practice; dietary; disability; effective therapy; exercise training; food consumption; heart function; high salt diet; improved; in vivo; indexing; insight; insulin sensitivity; kidney dysfunction; mortality; novel strategies; pre-clinical; preclinical study; pressure; prevent; programs; receptor; renal artery; research clinical testing; salt intake; salt sensitive hypertension; screening; sex; sexual dimorphism; soft drink; sugar; sweetened beverage

Program Director/Principal Investigator (Last, First, Middle): Rossi, Noreen F. Nearly half of US adults have hypertension. Fructose intake predisposes to salt-sensitive hypertension, an independent risk factor for major adverse cardiovascular events (MACE) and chronic kidney disease (CKD). Increased salt intake impairs vascular compliance even before frank hypertension develops. Aortic stiffness is now recognized as a robust predictor of MACE and CKD. Sympathoexcitation increases cardiovascular risk and strongly impacts aortic stiffness. Our preliminary data show that combined fructose and salt intake contributes to insulin resistance and hypertension that displays increased renal sympathetic activity and aortic as well as renal artery stiffness. The goal of this application is to achieve early identification and timely intervention of vascular stiffness to mitigate MACE and CKD. Robust, rigorous preclinical data are needed to justify testing and treatment. Our central hypothesis is that a diet moderately high in fructose and salt (FHS) results in hypertension, vascular stiffness and renal dysfunction driven by sympathetic nerve activity (SNA) and/or the renin-angiotensin- system (RAS). We propose to interrogate the mechanism that this neuroexcitation and increased RAS are driven by afferent inputs from the kidney to the brain at the subfornical organ and, thence, to SNA and/or angiotensinergic inputs to heart, vasculature and kidney. Direct interruption of the afferent renal nerves, SNA or pharmacological inhibition of SNA or RAS, alone or in combination, will decrease blood pressure, conduit vascular compliance, and ameliorate cardiac and renal function. We propose three aims: 1) ascertain the respective contribution of afferent vs efferent renal nerves on blood pressure, LV function, vascular compliance, and renal function in FHS rat model, 2) assess the impact of acute or chronic pharmacologic blockade of SNA and/or RAS on LV function, vascular compliance and renal function in FHS rats, and 3) evaluate the contribution of the arterial baroreflex, AT1R and TNFR1 in the subfornical organ that lies outside the blood brain barrier on blood pressure, LV-GLS, PP, PWV, RRI and renal function in rats on FHS diet. RAS and aortic compliance display sexual dimorphism, so we will evaluate Sprague Dawley rats of both sexes. We will use state-of-the-art ultrasonography, real-time renal blood flow and FITC-sinistrin measurements of glomerular filtration rate to assess aortic and renal artery compliance, LV and renal function. We will directly assess the impact of afferent and efferent renal nerves with selective deafferentation vs total denervation in conscious rats. We will validate the in vivo findings by ex vivo myography of aortic rings and assess markers of oxidative stress in vasculature. We will test whether chronic pharmacologic therapies to inhibit sympathetic inputs and/or RAS will also achieve improvements in conduit vascular compliance, cardiac and renal function. Our studies will identify therapeutic interventions that can be translated to screening and treatment of humans with pre-diabetes and stage 1 hypertension to improve vascular and renal function to mitigate MACE and CKD. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目主任/主要研究者（最后，第一，中间）：罗西，诺琳F。 近一半的美国成年人患有高血压。果糖摄入易患盐敏感性高血压， 主要不良心血管事件（MACE）和慢性肾病（CKD）的独立风险因素。 盐摄入量增加损害血管顺应性，甚至在坦率的高血压发展。主动脉僵硬是 现在被认为是MACE和CKD的可靠预测因子。交感神经兴奋增加心血管风险， 强烈影响主动脉僵硬度。我们的初步数据显示，果糖和盐的摄入量 胰岛素抵抗和高血压，表现为肾交感神经活动和主动脉以及 肾动脉僵硬该应用程序的目标是实现早期识别和及时干预， 血管僵硬以减轻MACE和CKD。需要稳健、严格的临床前数据来证明测试的合理性， 治疗我们的中心假设是，果糖和盐（FHS）适度高的饮食会导致高血压， 交感神经活动（SNA）和/或肾素-血管紧张素- 系统（RAS）。我们建议询问这种神经兴奋和RAS增加的驱动机制 通过从肾脏到穹窿下器官处的大脑的传入输入，并从那里到SNA，和/或 血管紧张素能输入到心脏、脉管系统和肾脏。直接中断肾传入神经，SNA或 SNA或RAS的单独或组合的药理学抑制将降低血压， 血管顺应性，改善心肾功能。我们提出三个目标：1）确定 传入与传出肾神经对血压、LV功能、血管顺应性 和肾功能，2）评估SNA的急性或慢性药物阻断的影响 和/或RAS对FHS大鼠左室功能、血管顺应性和肾功能的影响，以及3）评估 动脉压力感受器反射，AT 1 R和TNFR 1在穹窿下器官，位于血脑屏障外， 血压、LV-GLS、PP、PWV、RRI和肾功能。RAS和主动脉顺应性 显示两性异形，因此我们将评估两种性别的Sprague道利大鼠。我们将使用最先进的 超声、实时肾血流和FITC-左司他丁测定肾小球滤过率， 评估主动脉和肾动脉顺应性、LV和肾功能。我们将直接评估传入的影响， 清醒大鼠选择性去传入与完全去传入的传出肾神经。我们将验证 通过主动脉环的离体肌造影术的体内发现，并评估血管系统中的氧化应激标志物。 我们将测试抑制交感神经输入和/或RAS的慢性药物治疗是否也能达到 导管血管顺应性、心脏和肾功能的改善。我们的研究将确定治疗 干预措施，可以转化为筛查和治疗人类糖尿病前期和阶段1 改善血管和肾功能，减轻MACE和CKD。 OMB编号0925-0001/0002（修订版03/2020批准至02/28/2023）页码继续格式页码