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

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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