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

基本信息

批准号：
10593164
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
项目类别：
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/10593164
关键词：
Ablation Acute Adult Aging Angiotensins Animal Model Aorta Attention Baroreflex Blood - brain barrier anatomy Blood Pressure Blood Vessels Brain Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cessation of life Chronic Chronic Kidney Failure Clinical Research Collaborations Conscious Consumption DOCA Data Deafferentation procedure Denervation Development Diet Diet Habits Disease Early Diagnosis Early identification Endothelium Event Exercise Fluorescein-5-isothiocyanate Fructose Functional disorder 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 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 Tumor Necrosis Factor Receptor Ultrasonography arterial stiffness attributable mortality blood pressure elevation blood pressure reduction 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 pharmacologic pre-clinical preclinical study pressure prevent programs receptor renal artery research clinical testing salt intake salt sensitive hypertension screening sex sexual dimorphism soft drink sweetened beverage

项目摘要

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

项目总监/首席研究员（最后、第一、中间）：Rossi, Noreen F. 近一半的美国成年人患有高血压。果糖摄入易导致盐敏感性高血压主要不良心血管事件（MACE）和慢性肾脏病（CKD）的独立危险因素。盐摄入量的增加甚至在高血压发生之前就会损害血管顺应性。主动脉僵硬度是现在被认为是 MACE 和 CKD 的稳健预测因子。交感神经兴奋会增加心血管风险强烈影响主动脉僵硬度。我们的初步数据表明，果糖和盐的摄入结合有助于胰岛素抵抗和高血压，表现出肾脏交感神经活动和主动脉以及肾动脉僵硬。该应用的目标是实现早期识别和及时干预血管僵硬度以减轻 MACE 和 CKD。需要可靠、严格的临床前数据来证明测试和治疗。我们的中心假设是，适度高果糖和盐 (FHS) 的饮食会导致高血压、由交感神经活动（SNA）和/或肾素-血管紧张素-驱动的血管僵硬和肾功能障碍系统（RAS）。我们建议探究这种神经兴奋和 RAS 增加的驱动机制通过从肾脏到穹窿下器官的大脑的传入输入，然后到 SNA 和/或血管紧张素能输入心脏、脉管系统和肾脏。直接阻断传入肾神经、SNA 或 SNA 或 RAS 的药理学抑制，单独或组合，将降低血压，管道改善血管顺应性，改善心肾功能。我们提出三个目标：1）确定传入肾神经与传出肾神经对血压、左心室功能、血管顺应性、和 FHS 大鼠模型中的肾功能，2) 评估急性或慢性 SNA 药物阻断的影响和/或 RAS 对 FHS 大鼠左心室功能、血管顺应性和肾功能的影响，以及 3) 评估其贡献位于血脑屏障外的穹窿下器官中的动脉压力反射、AT1R 和 TNFR1 FHS 饮食大鼠的血压、LV-GLS、PP、PWV、RRI 和肾功能。 RAS 和主动脉顺应性显示性别二态性，因此我们将评估两性的 Sprague Dawley 大鼠。我们将使用最先进的超声检查、实时肾血流量和肾小球滤过率 FITC-sinistrin 测量评估主动脉和肾动脉顺应性、左心室和肾功能。我们将直接评估传入的影响以及清醒大鼠中选择性传入神经阻滞与完全去神经支配的传出肾神经。我们将验证通过主动脉环的离体肌动描记术进行体内发现并评估脉管系统中氧化应激的标志物。我们将测试抑制交感神经输入和/或 RAS 的慢性药物疗法是否也能实现改善导管血管顺应性、心脏和肾功能。我们的研究将确定治疗方法可转化为糖尿病前期和第一阶段人类筛查和治疗的干预措施高血压，改善血管和肾功能，减轻 MACE 和 CKD。 OMB 编号 0925-0001/0002（修订版 03/2020 已批准至 02/28/2023）页面延续格式页面