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The role of soluble prorenin receptor in hypertension associated with obesity

Award Number: R01HL142969
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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The role of soluble prorenin receptor in hypertension associated with obesity - PROJECT SUMMARY/ABSTRACT The epidemic of obesity, currently affecting more than 36.5% of the population in the United States, has contributed to a rise in the prevalence of hypertension. We recently found that obesity stimulated the secretion of the soluble form of the prorenin receptor (PRR), sPRR, into plasma. While examining sPRR protein concentrations in tissues, we found an increase of sPRR protein levels in the liver, the adipose tissue and the kidney of control mice fed a high fat diet compared to mice fed a low fat diet. New preliminary data showed that the infusion of a recombinant mouse sPRR in mice fed a standard diet activated local and circulating RAS by increasing renal cortical angiotensinogen (AGT) and circulating renin levels. Consistent with those results, our new results demonstrated that elevated plasma sPRR in adipose PRR KO mice is associated with an increase of cortical angiotensin II levels in the kidney. Urinary vasopressin levels also increased significantly in these mice. Together with our prior work, these results raise the possibility that sPRR regulates the renin angiotensin system (RAS) and body fluid volume. To test this idea, 3T3-L1 cells and human HepG2 cells were incubated with increased concentration of recombinant mouse sPRR. We found that sPRR increased the expression of AGT gene in 3T3-L1 cells and the secretion of AGT in the media of human HepG2. In addition, the incubation with our sPRR neutralizing antibody decreased AngII levels in the media of 3T3-L1 cells. Because sPRR infusion in mice increased plasma renin levels, we also investigated whether sPRR regulated the expression of renin in kidney. Interestingly, we found that sPRR binds to the promoter of the renin gene. Thus, we propose that obesity stimulates sPRR production leading to hypertension through a mechanism that involves the activation of the RAS and increases AVP. We will test the hypothesis that tissue-derived sPRR mediates angiotensin II-induced hypertension associated with obesity, likely by amplifying the local AGT and renin response and increases urinary AVP. We will also investigate whether blocking sPRR can be used as a treatment for hypertension associated with obesity. Outcomes will demonstrate whether obesity is regulated through a previously unrecognized pathway represented by upstream control of RAS and AVP by sPRR. Our studies point to a unique functional role for sPRR in hypertension associated with obesity.


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 = -$7,555 )
2024	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	4	1/29/2024	NON-COMPETING CONTINUATION	-$7,555
														Subtotal = -$7,555

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	4	8/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $380,765 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	4	7/22/2021	NON-COMPETING CONTINUATION	$380,765
														Subtotal = $380,765

Issue Date FY: 2020 ( Subtotal = $380,765 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	3	6/18/2020	NON-COMPETING CONTINUATION	$380,765
														Subtotal = $380,765

Issue Date FY: 2019 ( Subtotal = $374,618 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	6/21/2019	NON-COMPETING CONTINUATION	$374,618
														Subtotal = $374,618

Issue Date FY: 2018 ( Subtotal = $374,618 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	7/13/2018	NEW	$374,618
														Subtotal = $374,618

Grand Total All Awards = $1,503,211

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The role of soluble prorenin receptor in hypertension associated with obesity

Award Number: R01HL142969

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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