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Gut Metabolites, T cells, and Salt-Sensitive Hypertension

Award Number: R01HL166458
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Gut Metabolites, T cells, and Salt-Sensitive Hypertension - SUMMARY Hypertension is a primary modifiable risk factor for cardiovascular, cerebrovascular, and renal disease, and is the largest individual contributing factor to disease and mortality in the world. Salt-sensitive hypertensive individuals, who comprise 30-50% of the hypertensive population, have greater mortality than subjects with salt- resistant hypertension and exhibit renal end-organ damage. Immunity and inflammation are implicated in hypertension and renal damage in humans and experimental animal, but the mechanisms triggering immunity in hypertension are not understood. Dietary components other than salt can also play an important role in the development of cardiovascular disease and hypertension. Interestingly, an inverse relationship has been demonstrated between plant protein intake and blood pressure, ultimately associating health benefits with greater plant protein consumption. We recently discovered a novel link between dietary protein intake, immune- activation, and hypertension in the Dahl Salt-Sensitive (SS) rat, a rodent model of human disease. The experiments in this proposal will test the overarching hypothesis that free radical production from phagocytic NOX2 in infiltrating CD4+ T cells in the kidney of Dahl SS leads to an inappropriate elevation of renal vascular resistance (RVR), a reduction in glomerular filtration rate (GFR), the retention of sodium, and the further development of hypertension following high salt feeding. As a corollary to this hypothesis, we propose that the microbial metabolite carnitine, released by consumption of animal-based diets, upregulates NOX2 in T cells and amplifies salt-sensitive hypertension. In contrast, the metabolite propionate, released from consumption of grain- based diets, downregulates NOX2 and diminishes the full amplitude of salt-sensitive hypertension. The hypothesis will be addressed in two specific aims. Aim 1 will address the mechanisms whereby alterations in dietary protein source affect the release of metabolites from the gut microbiota and determine the influence of these metabolites on NOX2 in T cells and in the development of salt-sensitive hypertension. Aim 2 will address the role of phagocytic NOX2 in CD4+ T cells as a mediator of inappropriately increased renal vascular resistance and the development of salt-sensitive hypertension in Dahl SS by adoptive transfer of either wild type or NOX2- deficient CD4+ T cells into SS rats lacking T cells. This work will transform the understanding of salt-sensitive hypertension by utilizing novel animal models and approaches to demonstrate the mechanisms whereby dietary protein intake modifies immune mechanisms which serve to amplify disease severity. These studies should reveal new paradigms and provide insight with the potential to transform clinical/therapeutic approaches for the treatment of salt-sensitive hypertension.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $629,859 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	1/3/2025	NON-COMPETING CONTINUATION	$566,873
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	8/19/2025	NON-COMPETING CONTINUATION	$62,986
														Subtotal = $629,859

Issue Date FY: 2024 ( Subtotal = $617,262 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$50,389
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	12/26/2023	NON-COMPETING CONTINUATION	$566,873
														Subtotal = $617,262

Issue Date FY: 2023 ( Subtotal = $558,879 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	12/27/2022	NEW	$558,879
														Subtotal = $558,879

Grand Total All Awards = $1,806,000

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Gut Metabolites, T cells, and Salt-Sensitive Hypertension

Award Number: R01HL166458

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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