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Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension

Award Number: R01HL151587
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 Salt-sensitive hypertension is a significant health problem worldwide and there is a need to understand the underlying molecular mechanisms to enable more effective treatments. The proposed studies are based on a strong scientific foundation with experiments performed in our laboratories in Dahl salt-sensitive (SS) rats which mimic the human condition of the disease. We have demonstrated that this form of hypertension is associated with excess renal and vascular reactive oxygen species (ROS) production and reduced ability to excrete Na+. Excess reabsorption occurs in the renal medullary thick ascending limb (mTAL) leading to greater reabsorption of filtered Na+. Most relevant to this grant, SS rats exhibit a reduced ability to generate ATP through mitochondrial respiration in the mTAL, the tubular segment that is responsible for reabsorption of nearly 25% of the filtered Na+ of the kidney. In this region of the kidney, there exists high levels of oxidative stress (excess ROS production) emanating from both the mitochondria and cell membrane NADPH oxidases (NOX2 and NOX4). Two of the major gaps that remain in this field are first a lack of mechanistic studies of cellular/mitochondrial metabolism, and second, an absence of approaches to quantitatively evaluate the interdependence of the complex cellular processes. We hypothesize that a high salt diet which increases the delivery of Na+ to the mTAL of SS rats results in excess Na+ reabsorption and an increase of mTAL cytosolic [Na+] which stimulates mitochondrial ATP synthesis and ROS production which in turn stimulates membrane NOXs (ROS-ROS crosstalk and vicious cycle) leading to uncoupling of mitochondrial oxidative phosphorylation (OxPhos) and tissue injury. Aim 1 will utilize intact microdissected mTAL to test the hypothesis in SS rats that high salt diet increases cytosolic [Na+] thereby stimulating mitochondrial ROS production which in turn enhances greater uptake of Na+ into the cell and though ROS-ROS crosstalk of mitochondria and membrane NOX2 and NOX4 which amplifies total intracellular ROS production leading to OxPhos uncoupling. Contribution of membrane NOXs and mitochondrial ROS interactions will be determined using novel genetically engineered knockout strains SSNox4KO and SSp67/Nox4DKO rats. Aim 2 will determine the progression of the postulated bioenergetic events in isolated mitochondria of the kidney (both outer medulla and cortex) of high salt fed SS rats. Progressive alterations of mitochondrial bioenergetics and ROS production will be determined at four time points during the three weeks of high salt feeding. Aim 3 will utilize the measured data-driven computational modeling to provide a quantitative, integrated, and mechanistic framework that can predict the complex relationships existing between cellular oxygen utilization, energy production, and oxidative stress in the kidney during the development 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: 2024 ( Subtotal = $547,447 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	4	11/24/2023	NON-COMPETING CONTINUATION	$547,447
														Subtotal = $547,447

Issue Date FY: 2023 ( Subtotal = $608,274 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	3	2/11/2023	NON-COMPETING CONTINUATION	$60,827
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	3	11/18/2022	NON-COMPETING CONTINUATION	$547,447
														Subtotal = $608,274

Issue Date FY: 2022 ( Subtotal = $608,274 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$60,830
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	11/18/2021	NON-COMPETING CONTINUATION	$547,444
														Subtotal = $608,274

Issue Date FY: 2021 ( Subtotal = $608,274 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	001	1	1/13/2021	NEW	$7,018
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	12/23/2020	NEW	$540,428
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	002	1	8/5/2021	NEW	$60,828
														Subtotal = $608,274

Grand Total All Awards = $2,372,269

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Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension

Award Number: R01HL151587

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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