Tuesday, August 19, 2025 8/19/2025

Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control

Award Number: R01DK125464
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/03/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control - Hypertension remains a major public health challenge worldwide despite the abundance of available therapeutic options. Inappropriate therapy and patient non-compliance are the main factors accounting for poor blood pressure (BP) control. Identification of the mechanisms responsible for elevation of BP in specific patient cohorts is critical to effectively combat hypertension and related diseases. Excessive sodium retention via the Epithelial Na• Channel (ENaC) hampers the ability of the kidney to make precise adjustments to sodium balance and is a common pathogenic determinant of hypertension. Cumulative evidence suggests that biological sex is a pivotal covariate affecting the development and pathophysiology of hypertension in the human population and animal models. Our proposal introduces a novel concept that regulation of Na• reabsorption in the kidney and renal BP control rely on sex-specific mechanisms governing ENaC activity in the aldosterone-sensitive distal nephron. We and others have previously shown that aldosterone antagonism with mineralocorticoid receptor (MR) inhibitors is insufficient to reduce excessive renal ENaC activity and fails to effectively attenuate BP in male rodents with angiotensin II (Angil) dependent hypertension. Our pilot experiments reveal that hypertensive female rats with salt-sensitive and Angil-dependent hypertension benefit from MR antagonism and exhibit a stronger BP reduction, when compared to males. MR blockade is also much more potent at decreasing renal ENaC activity in Ang II-infused female rats than in males. Our findings strongly suggest that sensitivity of renal ENaC to aldosterone is an unrecognized sex-specific mechanism of chronic BP regulation. The proposal is built around the central hypothesis that hypersensitivity of ENaC to aldosterone accounts for a prevalent contribution of aldosterone to renal BP control in hypertensive female rats, when compared to males. We propose to test the hypothesis with two complementary specific aims addressing a clinically relevant problem of adequate blood pressure control at the molecular, cellular {Aim 1) and integrative {Aim 2) levels. Aim 1 will test the hypothesis that sensitivity of renal ENaC to aldosterone is greater in hypertensive female rats than in males. Our hypothesis predicts that female sex steroids positively modulate MR-dependent signaling in the kidney to augment the response of ENaC to aldosterone in hypertensive females. Aim 2 will test the hypothesis that aldosterone dominates renal BP control in hypertensive female, but not in male, rats. Our hypothesis predicts that aldosterone-MR axis is the primary driver of hypertension and renal damage in females and MR antagonism will be dramatically more effective at reducing BP and renal injury in hypertensive females than in males. Successful completion of this proposal will differentiate the pathophysiological mechanisms governing Na• retention in hypertensive males and females and provide the missing pre-clinical evidence to optimize the use of MR antagonists in hypertensive patients of both sexes.


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 = $366,405 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/18/2025	NON-COMPETING CONTINUATION	$366,405
														Subtotal = $366,405

Issue Date FY: 2024 ( Subtotal = $349,796 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/5/2024	NON-COMPETING CONTINUATION	$349,796
														Subtotal = $349,796

Issue Date FY: 2023 ( Subtotal = $366,405 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/31/2023	NON-COMPETING CONTINUATION	$366,405
														Subtotal = $366,405

Issue Date FY: 2022 ( Subtotal = $395,172 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/11/2022	NON-COMPETING CONTINUATION	$395,172
														Subtotal = $395,172

Issue Date FY: 2021 ( Subtotal = $456,165 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/3/2021	NEW	$456,165
														Subtotal = $456,165

Grand Total All Awards = $1,933,943

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Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control

Award Number: R01DK125464

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/03/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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