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Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension

Award Number: R01HL148114
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY There is no specific treatment available for the subpopulation of patients with salt sensitivity of blood pressure (BP); unfortunately, the molecular mechanisms underlying salt-sensitivity remain poorly understood. One of the major proposed mechanisms for the development of salt-sensitive (SS) hypertension involves a defect in the ability of the kidneys to excrete salt. Atrial Natriuretic Peptide (ANP) encoded by Nppa, is a hormone known to promote salt excretion and BP reduction, and there are clinical data implicating inherently low levels of ANP in the development of SS hypertension. Among other effects, ANP (via cGMP-related mechanisms) is known to be beneficial for mitochondrial bioenergetics and biogenesis. However, there is a gap in knowledge regarding the effects of ANP on mitochondria in the kidney, especially in SS hypertension. Our pilot studies demonstrated that during a high salt challenge Nppa-/- (ANP knockout) Dahl SS rats exhibit exacerbated salt-sensitivity, reduced sodium excretion, and aggravated kidney injury, which is associated with mitochondrial damage and dysfunction. We also showed that there is dysregulation of renal sodium transporters, in the Nppa-/- rats compared to wild-type controls, and the activity of the Epithelial Na+ Channel (ENaC) is elevated in the collecting ducts. Chronic ANP infusion in wild-type SS rats resulted in a dramatic attenuation of salt-induced BP increase and alleviated organ damage. We hypothesize that in SS hypertension ANP deficiency/reduced sensitivity to ANP is causative to renal mitochondrial dysfunction and associated sodium transport imbalance. To address the central hypothesis of this project, we developed three specific aims: Aim 1. Establish whether increased ANP levels are beneficial for renal salt handling and cardiac function in SS hypertension. Aim 2. Determine whether low renal cGMP level resulting from lack of ANP causes an increase in renal mitochondrial Ca2+ and reactive oxygen species (ROS). Aim 3. Test the hypothesis that disrupted Ca2+ balance and excessive ROS production by dysfunctional mitochondria affect renal sodium handling in SS hypertension. We generated abundant evidence to support these aims, created a rigorous and comprehensive experimental design and established novel cutting-edge techniques to address the hypothesis. We recruited strong collaborative expertise, and will implement a combination of whole-animal studies and in vivo techniques (blood pressure monitoring with drug infusion, metabolic studies and GFR measurements), electrophysiology (single channel and whole-cell patch-clamp of the freshly isolated nephrons and isolated mitochondria), advanced microscopy, mitochondrial spectrofluorimetry and respirometry, and routine molecular biology approaches. The successful completion of the proposed studies will unravel the novel causative mechanisms of salt-sensitivity.


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: 2024 ( Subtotal = $514,879 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$514,879
														Subtotal = $514,879

Issue Date FY: 2023 ( Subtotal = $525,386 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	4	7/18/2023	NON-COMPETING CONTINUATION	$525,386
														Subtotal = $525,386

Issue Date FY: 2022 ( Subtotal = $456,487 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	004	3	8/4/2022	NON-COMPETING CONTINUATION	$525,386
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	002	2	11/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$103,976
2022	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	001	1	11/5/2021	SUPPLEMENT FOR EXPANSION	-$26,968
2022	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	003	2	5/17/2022	SUPPLEMENT FOR EXPANSION	-$68,899
2022	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	000	1	11/5/2021	NEW	-$77,008
														Subtotal = $456,487

Issue Date FY: 2021 ( Subtotal = $709,863 )
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	000	1	5/7/2021	SUPPLEMENT FOR EXPANSION	$26,968
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	2	8/19/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$569,432
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	003	1	9/10/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	004	2	9/10/2021	SUPPLEMENT FOR EXPANSION	$113,463
2021	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	002	1	9/10/2021	NEW	$0
														Subtotal = $709,863

Issue Date FY: 2020 ( Subtotal = $553,474 )
2020	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Cardiovascular Diseases Research	000	1	8/14/2020	NEW	$553,474
														Subtotal = $553,474

Grand Total All Awards = $2,760,089

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Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension

Award Number: R01HL148114

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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