Wednesday, December 4, 2024 12/4/2024

Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure

Award Number: R01DK114663
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary One hallmark feature of chronic heart failure (CHF) is sodium and fluid retention. While the cardio-renal syndrome has been recognized, a comprehensive understanding of the precise cellular mechanisms contributing to sodium and water retention in CHF remains elusive. Renal denervation (RDN) has been shown to reduce sodium retention in rats and dogs with CHF. One of the key elements involved in renal sodium retention is activation of epithelial sodium channels (ENaC) of principal cells in the collecting tubule. We have previously shown that ENaC subunit expressions and activity were increased in the kidneys from rats with CHF. We have recent evidence indicating that increased proteases in the tubular fluid may contribute to the enhanced renal ENaC activity, providing a novel mechanistic insight for sodium retention commonly observed in CHF. We have observed that in rats with CHF: 1) the levels of serine proteases were dramatically increased in the urine; 2) protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Furthermore, our preliminary data have shown that RDN decreased the levels of proteases in the urine, reduced protein expressions of ENaC subunits in the kidney of CHF rats, supporting the potential role of sympathetic nerve activation. Based on these data, we will test the hypothesis that RDN reduces renal sodium retention in CHF rats by modulation of the ENaC and protease-ENaC axis. In AIM 1 we will determine the contribution of RDN in the expression/inactivation of ENaC in rats with CHF rats. In AIM 2 we will determine the contribution of tubular proteases in activating ENaC in rats with CHF. These aims will be addressed in rats with CHF using complementary methodologies ranging from cellular to the whole animal level, including physiological measurement of sodium balance, ENaC activity, eletrophysiological recording, protease and ubiquitination of ENaC using molecular biology techniques. The successful completion of the proposed studies will provide significant new information and insight into the contribution of ENaC regulation in altered sodium balance in CHF and the therapeutic benefits of RDN on sodium fluid retention, endemic to CHF.


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 = -$40,565 )
2025	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/16/2024	NON-COMPETING CONTINUATION	-$40,565
														Subtotal = -$40,565

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $414,955 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/28/2021	NON-COMPETING CONTINUATION	$414,955
														Subtotal = $414,955

Issue Date FY: 2020 ( Subtotal = $414,955 )
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/27/2020	NON-COMPETING CONTINUATION	$414,955
														Subtotal = $414,955

Issue Date FY: 2019 ( Subtotal = $414,955 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/2/2019	NON-COMPETING CONTINUATION	$414,955
														Subtotal = $414,955

Issue Date FY: 2018 ( Subtotal = $414,712 )
2018	2018	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/9/2018	NON-COMPETING CONTINUATION	$414,712
														Subtotal = $414,712

Issue Date FY: 2017 ( Subtotal = $412,444 )
2017	2017	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/15/2017	NEW	$412,444
														Subtotal = $412,444

Grand Total All Awards = $2,031,456

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Novel Target Mechanism (Renal Denervation) to Reduce Sodium Retention in Chronic Heart Failure

Award Number: R01DK114663

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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