Inorganic phosphates (Pi) are widely used in the food industry as preservatives. High Phosphate (Pi) intake is a well-recognized contributor to vascular calcification and cardiovascular mortality in patients with renal failure. More recently, a high Pi diet was shown to trigger BP elevation even in rodents with normal kidneys. Mechanisms underlying detrimental effects of high Pi diet are complex and largely unknown but our recent study in rats have identified novel mechanisms mediating Pi-induced hypertension (HTN) and left ventricular hypertrophy via overactivation of the sympathetic nervous system. Our data also suggest that animals fed a high Pi but constant sodium intake have an elevated cerebrospinal fluid content of fibroblast growth factor 23 (FGF23, a key hormone in Pi homeostasis), and reduced expression within the central nervous system (CNS) of Klotho (a key protein in Pi homeostasis). Klotho has also been shown to increase nitric oxide (NO) production in the vasculature. In the CNS, it has been established that NO produced by the neuronal form of nitric oxide synthase (nNOS) plays a major inhibitory role on central sympathetic outflow. Klotho expression was shown to increase after regular exercise in mice and humans. However, the role of dietary Pi, Klotho, and FGF23 in the neural control of blood pressure (BP) has not been investigated. Thus, we propose parallel translational studies in normal rats and prehypertensive humans (BP 120-129/80-84 mmHg) to systematically investigate the influence of dietary Pi on sympathetic nervous system and BP regulation. The proposed studies are innovative in that they maintain the potential to shift current clinical practice paradigms by identifying phosphate as a key modifiable risk factor for the prevention and treatment of hypertension. The ultimate results of our work could lead to more effective strategy in reducing the global burden of hypertension and target organ complications. We envision this work advancing the field in several important ways: (1) translating work from rodent models to human hypertension, using of the state-of-the-art techniques of microneurography; (2) examining the role of dietary phosphate in neural control of BP both at rest and during exercise, which has not been previously addressed; (3) demonstrating the role of inorganic phosphate in regulating BP via alteration in the concentration of soluble klotho or FGF23 in the central nervous system, (4). Establishing a new role of exercise training in preventing phosphate-induced sympathetic overactivation and hypertension, and (5). Establishing a novel role of FGF receptor in the central nervous system in mediating phosphate- induced hypertension.

Public Health Relevance

Inorganic phosphates (Pi) are widely used in the food industry as preservatives. High Phosphate (Pi) intake is a well-recognized contributor to vascular calcification and cardiovascular mortality in patients with renal failure. More recently, a high Pi diet was shown to trigger BP elevation even in rodents with normal kidneys. The current proposal aims to examine the mechanisms of Pi-induced hypertension and its relevance in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL133179-01A1
Application #
9309263
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Maric-Bilkan, Christine
Project Start
2017-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$792,454
Indirect Cost
$303,285
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Vongpatanasin, Wanpen; Ayers, Colby; Lodhi, Hamza et al. (2018) Diagnostic Thresholds for Blood Pressure Measured at Home in the Context of the 2017 Hypertension Guideline. Hypertension 72:1312-1319