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Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension

Award Number: K01DK126792
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/08/2025
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension - PROJECT SUMMARY Individuals with type II diabetes (T2DM) and metabolic syndrome (MS) display decreased activity of peroxisome proliferator activated receptor gamma (PPARγ) and often develop salt-sensitive hypertension (SS HT). PPARγ activation by thiazolidinediones (TZDs) lowers blood pressure in T2DM and MS. Moreover, PPARγ impairment caused by dominant negative mutations (e.g. P467L) that block PPARγ activation by ligands cause severe early onset HT in humans, while selective expression of these mutations in vascular smooth muscle (VSM) recapitulates human HT in mice (S-P467L), suggesting impairment of vascular PPARγ is causal. Using S-P467L mice as a model of vascular PPARγ impairment, I have provided compelling preliminary data supporting an innovative concept that the detrimental effects of PPARγ impairment in VSM may be mediated by enhanced PGE2/E-Prostanoid Receptor 3 (EP3) signaling in pre-glomerular resistance vessels (interlobular artery and afferent arterioles), causing increased renal vascular resistance and blunted renal blood flow during excess salt loading. The blunted renal perfusion is associated with decreased intrarenal nitric oxide (NO) bioavailability and increased sodium retention in S-P467L mice fed a 4% high salt diet. We and others have previously published that vascular PPARγ prevents oxidative stress through transcriptional regulation of antioxidant genes. Loss of PPARγ-mediated antioxidant responses may decrease NO bioavailability in renal microvessels through an imbalance between NO and reactive oxygen species such as superoxide. The goal of this K01 award is to investigate the renal mechanisms of salt sensitivity caused by the impairment of vascular PPARγ. Aim 1 will test the hypotheses that a) impairment of vascular PPARγ blunts renal blood flow by enhancing PGE2/EP3 signaling in renal microvessels, and b) pharmacological inhibition of EP3 decreases renal vascular resistance, improves renal perfusion, and attenuates SS HT during PPARγ impairment. Aim 2 will test the hypotheses that a) impaired vascular PPARγ results in decreased NOS-mediated NO generation and/or impaired antioxidant defense in the kidney, and b) intrarenal NO deficiency impairs natriuresis and contributes to SS HT during PPARγ impairment. Successful completion of the mentored scientist development grant will allow me to acquire necessary skills and expertise to transition to independence in the academia of hypertension research focusing on renal vascular biology, redox biology, and tubular physiology.


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 = $153,846 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	5/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$135
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,846
2025	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/25/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/28/2025	NON-COMPETING CONTINUATION	-$135
														Subtotal = $153,846

Issue Date FY: 2024 ( Subtotal = $153,846 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/15/2023	NON-COMPETING CONTINUATION	$153,846
														Subtotal = $153,846

Issue Date FY: 2023 ( Subtotal = $153,846 )
2023	2023	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/22/2022	NON-COMPETING CONTINUATION	$153,846
2023	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $153,846

Issue Date FY: 2022 ( Subtotal = $153,846 )
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	4/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$14,891
2022	2022	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,846
2022	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	4/8/2022	NEW	-$14,891
2022	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	3/14/2022	NEW	$0
														Subtotal = $153,846

Issue Date FY: 2021 ( Subtotal = $106,102 )
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	1/6/2021	NEW	$106,102
														Subtotal = $106,102

Grand Total All Awards = $721,486

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Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension

Award Number: K01DK126792

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/08/2025

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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