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Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

Award Number: R01DK126452
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation - Epidemiological and outcomes studies in patients, as well as studies in rodent models, reveal that renal ischemic kidney injury and unilateral obstructive uropathy brings on long-term consequences: hypertension and chronic kidney disease. Major pathophysiological contributors include impaired renal hemodynamics, endothelial dilator dysfunction, and endothelial cell inflammation. Because the renal microcirculation lacks efficient regenerative capacity, acute damage to the microcirculation can lead to long-term changes in renal hemodynamics that predispose patients to hypertension and chronic kidney disease. A class of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs) increase renal blood flow and improve endothelial cell function. Not known is the contribution of CYP2C epoxygenases, soluble epoxide hydrolase (sEH), and regioisomeric EETs to salt-sensitive hypertension and chronic kidney disease following obstructive uropathy and renal ischemic injury. We hypothesize that decreased endothelial EET levels result in endothelial dysfunction and impaired renal hemodynamics following renal ischemic injury or urinary tract obstruction. The immediate goals of this project are to determine the ability for endothelial EETs to improve endothelial- dependent afferent arteriolar dilation, to decrease endothelial inflammation, and to prevent salt-sensitive hypertension and chronic kidney disease following unilateral ureter obstruction (UUO) or ischemia/reperfusion (I/R) kidney injury. This project will utilize pharmacological as well as global and tissue-specific genetic manipulation of CYP2C, sEH, and EETs. We will obtain our immediate goals by completing three aims. Aim 1 will test the hypothesis that decreased EET levels or EET function contributes to the development of salt- sensitive hypertension and chronic kidney disease following UUO or I/R kidney injury. Aim 2 will test the hypothesis that increasing endothelial EET levels will improve renal microvascular endothelial function following UUO or I/R kidney injury to prevent salt-sensitive hypertension and chronic kidney disease. Aim 3 will test the hypothesis that pharmacological approaches to increase EET levels can prevent the long-term salt-sensitive hypertensive and chronic kidney injury following UUO or I/R kidney injury. Accordingly, our findings promise to advance the field forward by not only enhancing our understanding of the pathophysiological mechanisms whereby UUO or I/R kidney injury leads to chronic kidney disease but also leading to new therapeutic treatments.


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 = $0 )
2025	2022	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/13/2025	NON-COMPETING CONTINUATION	-$175,856
2025	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	1/13/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$261,414
2025	2021	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/13/2025	NEW	-$85,558
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $494,087 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/16/2024	NON-COMPETING CONTINUATION	$494,087
														Subtotal = $494,087

Issue Date FY: 2023 ( Subtotal = $497,642 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/16/2023	NON-COMPETING CONTINUATION	$514,673
2023	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/31/2023	NON-COMPETING CONTINUATION	-$346,685
2023	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$329,654
														Subtotal = $497,642

Issue Date FY: 2022 ( Subtotal = $522,541 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$522,541
														Subtotal = $522,541

Issue Date FY: 2021 ( Subtotal = $562,842 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/31/2021	NEW	$562,842
														Subtotal = $562,842

Grand Total All Awards = $2,077,112

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Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

Award Number: R01DK126452

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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