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T cell homing to the kidney contributes to salt retention and blood pressure regulation

Award Number: R01HL146713
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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T cell homing to the kidney contributes to salt retention and blood pressure regulation - PROJECT SUMMARY / ABSTRACT Hypertension is a prominent public health problem and a major risk factor for other cardiovascular diseases. Major clinical challenges in the management of hypertension are insufficient blood pressure control and the recurrence of hypertension after discontinuing medications. Thus, it is important to identify the unknown mechanisms that drive its pathogenesis. Immune cells, particularly CD8+ T cells (CD8Ts), play a crucial role in hypertension. Our recent findings revealed inappropriate activation and infiltration of CD8Ts into the kidneys during the initial elevation of blood pressure, which exacerbated hypertension by enhancing renal salt retention. However, the underlying mechanisms driving this inappropriate CD8T activation in hypertension remain unclear, hindering the development of effective treatment strategies. Our initial studies showed that CD8T activation in hypertension does not necessitate specific antigens, suggesting an antigen-independent mechanism. Building on this premise, we hypothesize in this competing renewal application that P2X7-mediated calcium influx activates CD8Ts during the onset of hypertension, and this event is sustained by an extracellular ATP autocrine positive feedback loop. Moreover, this process promotes the formation of kidney resident memory CD8Ts (kidney-CD8Trms), thereby intensifying the progression of hypertension and hypertensive memory of salt sensitivity. Specifically, Aim 1 will test the mechanism of P2X7-mediated antigen-independent activation of CD8Ts in hypertension and the critical role of the autocrine positive feedback loop in maintaining this CD8T activation to become long-lasting. Aim 2 will determine the underlying mechanisms and critical molecular pathways that mediate the establishment of CD8Trms in the kidney during the development of hypertension. Proof-of-principle studies in Aim 2 will determine whether kidney-CD8Trms contribute to the memory of salt sensitivity that underlies the recurrence of hypertension. Our experiments will rely on genetically modified animals including a knockout of purinergic receptor P2X7, CD8T-specific gene deletion of pannexin 1 (Panx1), and T cell-specific knockout of transforming growth factor β (TGFβ) to implicate these molecules in the activation and establishment of kidney-CD8Trms that fuel the progression of hypertension and hypertensive memory of salt sensitivity. Vertical integration of complementary in vitro and in vivo studies are further incorporated into this proposal to elucidate the important molecular mechanisms that cause T cell activation and homing to the kidney, thus impairing salt and volume homeostasis to cause hypertension and its recurrence. We propose that salt- sensitive hypertension is caused and maintained, at least in part, by a resident memory immune disorder in the kidney. Moreover, the key molecules identified in this study may represent novel targets for future immunotherapies to mitigate hypertension and its recurrence.


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 = $685,749 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	002	7	3/28/2025	NON-COMPETING CONTINUATION	$685,749
2025	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	001	6	3/18/2025	COMPETING CONTINUATION	$254
2025	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	5	3/18/2025	NON-COMPETING CONTINUATION	-$254
														Subtotal = $685,749

Issue Date FY: 2024 ( Subtotal = $761,943 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	6	4/10/2024	COMPETING CONTINUATION	$685,749
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	001	6	7/4/2024	COMPETING CONTINUATION	$76,194
														Subtotal = $761,943

Issue Date FY: 2023 ( Subtotal = $380,000 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	5	3/24/2023	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $380,000

Issue Date FY: 2022 ( Subtotal = $380,000 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	001	4	6/29/2022	NON-COMPETING CONTINUATION	$38,000
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	4	4/11/2022	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $380,000

Issue Date FY: 2021 ( Subtotal = $380,000 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	3	4/16/2021	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $380,000

Issue Date FY: 2020 ( Subtotal = $379,375 )
2020	2020	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	2	3/23/2020	NON-COMPETING CONTINUATION	$379,375
														Subtotal = $379,375

Issue Date FY: 2019 ( Subtotal = $376,875 )
2019	2019	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cardiovascular Diseases Research	000	1	3/6/2019	NEW	$376,875
														Subtotal = $376,875

Grand Total All Awards = $3,343,942

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T cell homing to the kidney contributes to salt retention and blood pressure regulation

Award Number: R01HL146713

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/10/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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