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：
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
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/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

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. 我们近一半的成年人患有高血压。果糖摄入易于盐敏感高血压，一种重大不良心血管事件（MACE）和慢性肾脏病（CKD）的独立危险因素。盐的摄入量增加在坦率的高血压发展之前会损害血管依从性。主动脉刚度是现在被认为是MACE和CKD的强大预测指标。交感神经增加心血管风险和强烈影响主动脉僵硬。我们的初步数据表明，果糖和盐摄入量合并有贡献胰岛素抵抗和高血压，显示出增加肾交感活性和主动脉的增加肾动脉刚度。此应用的目的是实现早期识别和及时干预血管刚度减轻狼牙棒和CKD。需要强大的严格临床前数据来证明测试和治疗。我们的中心假设是，饮食中适中的果糖和盐（FHS）导致高血压，由交感神经活动（SNA）和/或肾素 - 血管紧张素 - 系统（RAS）。我们建议询问这种神经兴趣和增加的RA的机制通过从肾脏到大脑的传入输入，从肾脏到大脑，然后再到SNA和/或血管紧张素对心脏，脉管系统和肾脏的输入。直接中断传入的肾神经，SNA或单独或组合的SNA或RAS的药理抑制作用将降低血压，导管血管依从性以及改善心脏和肾功能。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，血管依从性的贡献， FHS大鼠模型中的肾功能，2）评估SNA急性或慢性药理阻滞的影响和/或RAS关于LV功能，FHS大鼠的血管顺应性和肾功能，3）评估贡献属于血液脑屏障的supernical器官中的动脉压力反射，AT1R和TNFR1 血压，LV-GLS，PP，PWV，RRI和FHS饮食中的肾功能。 RAS和主动脉合规性显示性二态性，因此我们将评估两性的Sprague Dawley老鼠。我们将使用最先进的超声检查，实时肾脏血流和FITC - 固定蛋白测量肾小球过滤率评估主动脉和肾动脉依从性，LV和肾功能。我们将直接评估传入的影响和有意识大鼠的全部神经与完全神经的选择性肾神经。我们将验证在体内的体内发现，主动脉环的体内神秘图并评估脉管系统中氧化应激的标志物。我们将测试慢性药理疗法是否抑制交感神经输入和/或RAS也将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性可以将糖尿病前和第1阶段筛查和治疗的干预措施转化为对人类的筛查和治疗高血压以改善血管和肾功能以减轻MACE和CKD。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面