Hypertension is the leading cause of loss of health worldwide. As much as 50% of hypertension is salt- sensitive, a disease in which blood pressure (BP) increases with dietary salt due to a renal defect. Angiotensin II (Ang II) is a key regulator of BP primarily through actions on the kidney, including the proximal tubule (PT). The PT reabsorbs ~70% of the filtered Na via Na/H exchanger type 3 (NHE3) and Na/K ATPase. Ang II stimulates transport via activation of Ang II type 1 (AT1) receptors and classical protein kinase C (PKC) isoforms (?, ?, ?). Physiological concentrations of Ang II when animals are on normal salt maximally stimulate PT Na reabsorption. When dietary salt is elevated, Ang II levels fall by ~70%, urinary Na excretion (UNaV) increases and the salt is eliminated. However, if the effects of Ang II don't decline in the face of a high-salt diet, salt is retained and BP increases. More than 15 million Americans consume >20% of their calories as fructose. Dietary fructose causes hypertension in humans. We have shown that when rats consume 20% of their calories as fructose (20% fructose diet) they develop salt-sensitive hypertension, and that BP begins to increase 1-2 days after beginning a high-salt diet. AT1 receptor blockers reduce BP in fructose-fed rats; however, the role of the PT and the mechanisms by which fructose causes salt-sensitive hypertension are unknown. We show that fructose can activate PKC?/? in isolated, perfused PTs and that a 20% fructose, high- salt diet enables low concentrations of Ang II to stimulate PT transport measured in vitro, but does not enhance the maximum effect. Atrial natriuretic factor, dopamine, nitric oxide do not play a role. However, whether the effects of fructose on the PT contribute to fructose-induced salt-sensitive hypertension and the mechanisms involved are unknown. We hypothesize that a 20% fructose diet blunts salt-induced natriuresis and causes salt-sensitive hypertension by activating PKC? thereby enabling low concentrations of Ang II such as those caused by a high-salt diet to stimulate PT Na reabsorption.
Aim 1 will test whether a 20% fructose diet enables low concentrations of Ang II as caused by a high-salt diet to stimulate PT Na reabsorption by NHE3 and Na/K ATPase.
Aim 2 will test whether a 20% fructose diet raises basal PKC? activity thereby enabling low concentrations of Ang II to elevate PKC? activity sufficiently to stimulate Na reabsorption.
Aim 3 will test whether the effects of a 20% fructose diet on the PT reduce the ability to excrete a salt load and cause salt- sensitive hypertension. We will use state of the art techniques in imaging, physiology, molecular biology and gene transfer. This project will yield new insights into how dietary fructose causes salt-sensitive hypertension.

Public Health Relevance

Consumption of sugars, and specifically fructose, has increased dramatically over the past several years. Fructose consumption causes high blood pressure, liver failure, kidney damage and diabetes. Fructose increases salt reabsorption by the kidney; however how it does so is poorly understood. It is also unknown whether the effects fo fructose on the kidney cause high blood pressure. This proposal will study these problems.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Varagic, Jasmina
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Case Western Reserve University
Schools of Medicine
United States
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Khan, Shenaz; Cabral, Pablo D; Schilling, William P et al. (2018) Kidney Proximal Tubule Lipoapoptosis Is Regulated by Fatty Acid Transporter-2 (FATP2). J Am Soc Nephrol 29:81-91
Gonzalez-Vicente, Agustin; Garvin, Jeffrey L; Hopfer, Ulrich (2018) Transcriptome signature for dietary fructose-specific changes in rat renal cortex: A quantitative approach to physiological relevance. PLoS One 13:e0201293
Gonzalez-Vicente, Agustin; Hong, Nancy J; Yang, Nianxin et al. (2018) Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets. Nutrients 10:
Gonzalez-Vicente, Agustin; Hopfer, Ulrich; Garvin, Jeffrey L (2017) Developing Tools for Analysis of Renal Genomic Data: An Invitation to Participate. J Am Soc Nephrol 28:3438-3440
Gonzalez-Vicente, Agustin; Garvin, Jeffrey L (2017) Effects of Reactive Oxygen Species on Tubular Transport along the Nephron. Antioxidants (Basel) 6:
Gonzalez-Vicente, Agustin; Cabral, Pablo D; Hong, Nancy J et al. (2017) Dietary Fructose Enhances the Ability of Low Concentrations of Angiotensin II to Stimulate Proximal Tubule Na? Reabsorption. Nutrients 9: