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Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease

Award Number: F31DK127640
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease - PROJECT SUMMARY Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. Hyperphosphatemia and elevations in serum levels of the hormone fibroblast growth factor (FGF) 23 are a hallmark of CKD and associated with an increased risk of cardiac injury and death. We previously found that in rodents, hyperphosphatemia induced by the administration of a high-phosphate diet elevates serum FGF23 levels and causes cardiac hypertrophy in the absence of kidney damage, suggesting that elevated phosphate and/or FGF23 per se might act as circulating factors that can damage the heart. However, whether phosphate or FGF23 can directly target the heart and induce injury is unknown. FGF23 is mainly produced by bone, and we previously found that FGF23 can activate specific signaling events in cultured cardiac myocytes and induce hypertrophy. However, whether FGF23 can directly target cardiac myocytes in vivo remains unknown. Based on global FGFR4 deletion and pharmacological FGFR4 inhibition studies, we have recently identified FGFR4 as the FGF23 receptor that is required for the development of cardiac hypertrophy in animal models of CKD as well as in mice on high-phosphate diet. For the proposed study we have generated a novel mouse model for the cardiac myocyte-specific deletion of FGFR4. By inducing CKD via an adenine diet or by administration of a high- phosphate diet, we will be able to determine whether FGF23/FGFR4 activation in the heart is required for the development of cardiac injury. Furthermore, direct effects of phosphate on cardiac myocytes have not been studied to date. Our preliminary work indicates that elevations of extracellular phosphate levels in cardiac myocyte cultures induce pro-inflammatory signaling and osteogenic gene programs. Here we will determine whether these changes lead to pathologic cardiac remodeling in mice, including cardiac hypertrophy, fibrosis, inflammation and calcification. We also found that phosphate treatments of cultured cardiac myocytes induce the expression of FGF23 that under normal conditions is not found in the heart. It has been reported that in CKD the heart starts to produce FGF23. However, whether heart-derived FGF23 can cause cardiac remodeling, is unclear. To determine the consequences of cardiac FGF23 production, we will generate a new mouse model with cardiac myocyte-specific deletion of FGF23, followed by the administration of high-phosphate or adenine diets, and a detailed analysis of cardiac structure and function. Overall, our study is designed to test the hypothesis that hyperphosphatemia - by itself as well as in the context of CKD - contributes to cardiac injury by inducing FGF23 production in the heart. FGF23 is a potent pro-hypertrophic factor, and like circulating FGF23, paracrine FGF23 might directly target cardiac myocytes via FGFR4 and induce cardiac injury. We postulate that pharmacologic blockade of FGFR4 can inhibit the pathologic actions of FGF23 on the heart and thereby serve as a novel therapeutic strategy to prevent or treat CKD-associated cardiac injury and prolong survival.


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 = $48,974 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/9/2024	NON-COMPETING CONTINUATION	$47,694
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/26/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $48,974

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/23/2023	NON-COMPETING CONTINUATION	$47,694
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	5/23/2022	NEW	-$1
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/6/2022	NEW	$717
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/4/2022	NEW	$46,036
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/4/2022	NEW	$0
														Subtotal = $46,752

Grand Total All Awards = $143,420

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Hyperphosphatemia Contributes to Cardiac Injury in Chronic Kidney Disease

Award Number: F31DK127640

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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