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

项目主任/首席调查员(最后、第一、中间)：Rossi，Noreen F. 近一半的美国成年人患有高血压。摄入果糖易患盐敏感型高血压 重大不良心血管事件(MACE)和慢性肾脏疾病(CKD)的独立危险因素。 即使在出现明显高血压之前，盐摄入量的增加也会损害血管顺应性。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 会严重影响主动脉僵硬。我们的初步数据显示，果糖和盐的联合摄入量有助于 对胰岛素抵抗和高血压表现为肾交感神经活性增加和主动脉以及 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。需要强大、严谨的临床前数据来证明测试和 治疗。我们的中心假设是，果糖和盐(FHS)含量适度高的饮食会导致高血压， 交感神经活动(SNA)和/或肾素-血管紧张素致血管僵硬和肾功能障碍- 系统(RAS)。我们建议询问这种神经兴奋和增加的RAS被驱动的机制 通过从肾脏传入穹隆下器的大脑，并从那里传入SNA和/或 血管紧张素能传入心脏、血管系统和肾脏。直接阻断传入肾神经，SNA或 SNA或RAS的药物抑制，单独或联合使用，将降低血压 血管顺应性，并改善心脏和肾脏功能。我们提出了三个目标：1)确定 传入和传出肾神经对血压、左心功能、血管顺应性、 2)评价SNA急、慢性药物阻断对FHS大鼠肾功能的影响 和/或RAS对FHS大鼠左心功能、血管顺应性和肾功能的影响 位于血脑屏障外的穹隆下器官的动脉压力感受性反射、AT1R和TNFR1的表达 FHS饮食大鼠血压、LV-GLS、PP、PWV、RRI及肾功能。RAS与主动脉顺应性 表现出性别的二形性，所以我们将评估Spraogue Dawley大鼠的性别。我们将使用最先进的 超声、实时肾血流和FITC-Sinistrin测量肾小球滤过率 评估主动脉和肾动脉顺应性、左心功能和肾功能。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神经的传出肾神经比较。我们将验证 通过体外主动脉环的肌成像术和评估血管系统氧化应激的标记物的活体发现。 我们将测试抑制交感神经传入和/或RAS的慢性药物疗法是否也能达到 改善管道血管顺应性、心脏和肾脏功能。我们的研究将确定治疗方法 可转化为对糖尿病前期和1期患者进行筛查和治疗的干预措施 高血压可改善血管和肾功能，减轻MACE和CKD。 OMB编号0925-0001/0002(批准的第03/2020版至2023年2月28日)续页格式页

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