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Role of CTRP1 in Renal Sodium Handling in Obesity-Related Hypertension

Award Number: K99HL155850
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Role of CTRP1 in Renal Sodium Handling in Obesity-Related Hypertension - Project Summary Obesity and its adverse consequences are global public health concerns. Though we have achieved compelling advances, more effective strategies for managing obesity-associated diseases are still in high demand. Recently, accumulating evidence from human and animal studies indicate that a novel adipokine, C1q/TNF-related protein 1 (CTRP1), displays multiple beneficial effects on glucose and lipid disorders. This suggests immense potential for CTRP1 to serve as a novel therapeutic target for obesity-related metabolism disorders. However, the potential hypertensive effect of CTRP1 limits its application. Therefore, this proposal aims to understand the role of CTRP1 in obesity-related hypertension. Abnormal kidney function and its associated increases in sodium reabsorption serve as a fundamental mechanism in developing obesity-related hypertension. Nevertheless, no studies have been carried out to determine the role of CTRP1 in regulating renal sodium reabsorption and blood pressure during obesity. In preliminary studies, we discovered an undescribed direct regulatory effect of CTRP1 interaction with (pro)renin receptor (PRR) in controlling ENaC activation in vitro; this may be linked to Nox4-dependent H2O2 production. We presented further evidence that exogenous CTRP1 infusion reduced urinary sodium excretion and elevated blood pressure accompanied by increased circulating renin-angiotensin-aldosterone system (RAAS) activity in vivo. These results support the function of CTRP1 in regulating sodium reabsorption and blood pressure under basal conditions. Emerging evidence from clinical and animal studies reveal a positive correlation between plasma CTRP1 levels and body mass index or blood pressure. Thus, we hypothesize that CTRP1 plays a role in determining blood pressure during obesity via stimulating renal sodium reabsorption in two ways: 1) The local renal mechanism of PRR-dependent ENaC activation; 2) The systemic mechanism of circulating RAAS-dependent abnormal renal sodium handling. Three specific aims are designed to test this hypothesis. In Aim 1, we will employ multiple gene targeting techniques to determine the role of CTRP1 in renal sodium handling and blood pressure during obesity. In Aim 2, we will dissect CTRP1-induced signaling mechanisms involving coordinated activation of the PRR-dependent pathway and the Nox4/H2O2 pathway in controlling ENaC in cultured cells. In Aim 3, within adipocyte-specific CTRP1 deletion mice, we will identify the role of adipocyte- derived CTRP1 in circulating RAAS activation during obesity. Furthermore, we will explore the possibility of CTRP1 direct affecting renin synthesis or secretion in the juxtaglomerular apparatus by using an isolated perfused mice kidney model. New information from this proposal would greatly enhance our understanding of the role of CTRP1 in obesity-related hypertension and lead to novel therapies to manage obesity-related diseases.


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: 2023 ( Subtotal = -$26,020 )
2023	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	2	8/21/2023	NON-COMPETING CONTINUATION	-$26,020
														Subtotal = -$26,020

Issue Date FY: 2022 ( Subtotal = $90,000 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	2	12/20/2021	NON-COMPETING CONTINUATION	$90,000
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	2	8/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $90,000

Issue Date FY: 2021 ( Subtotal = $90,000 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	1	12/28/2020	NEW	$90,000
														Subtotal = $90,000

Grand Total All Awards = $153,980

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Role of CTRP1 in Renal Sodium Handling in Obesity-Related Hypertension

Award Number: K99HL155850

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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