Advisor(s)
Christian Faul
Kirk Habegger
Committee Member(s)
Glenn Rowe
Stefanie Krick
Takamitsu Saigusa
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Cell Biology
Date of Award
6-3-2025
Abstract
Chronic Kidney Disease (CKD) is a global health risk that increases patients’ risk for premature mortality and is accompanied by pathologic cardiac hypertrophy and fibrosis. Declining kidney function results in elevations of serum phosphate and Fibroblast Growth Factor (FGF) 23, a bone-derived phosphaturic hormone. Hyperphosphatemia and elevated FGF23 are associated with cardiovascular mortality in CKD. FGF23 can directly target cardiac myocytes via FGF Receptor (FGFR) 4 and induce cardiac hypertrophy and blocking FGFR4 signaling in CKD models reduces cardiac hypertrophy, but not fibrosis. FGF23 elevations are also observed following exercise and during pregnancy, two scenarios of physiologic hypertrophy not associated with cardiac damage. We sought to investigate if cardiac fibroblasts are responsive to FGF23, the source of FGF23 in the heart, and to identify if FGF23 is also involved in physiologic hypertrophy. We isolated adult mouse cardiac fibroblasts (AMCFs) from mice on normal or high phosphate diet. AMCFs from both diets were treated with FGF23 and did not experience proliferation, pro-fibrotic gene programs, or differentiation into myofibroblasts, but high phosphate AMCFs secreted FGF23. This implies that normal and high phosphate diet cardiac fibroblasts are not primed for FGF23 responsiveness and that FGF23/FGFR4 signaling is not a driver of cardiac fibrosis. We demonstrate that cardiac fibroblasts are not a target, but a source of FGF23. This cardiac-derived FGF23 may be able to contribute—in a paracrine manner—to cardiac hypertrophy in scenarios of elevated phosphate, such as CKD or intake of a phosphate-rich diet in excess. To determine whether FGF23/FGFR4 signaling contributes to physiologic cardiac hypertrophy, we studied pregnant wild-type and FGFR4 knockout mice (FGFR4−/−). In comparison to virgin littermates, pregnant wild-type and FGFR4−/− mice showed increases in serum FGF23 levels and heart weight. The increased myocyte area in pregnant wild-type hearts was absent from pregnant FGFR4−/− mouse hearts. In treatments of cultured cardiac myocytes with serum from fed pythons—another model of physiologic hypertrophy—FGFR4 inhibition abrogated the serum-induced hypertrophy. Our findings suggest that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to physiologic cardiac hypertrophy in a FGFR4-dependent manner.
ProQuest ID
Recommended Citation
Campos, Isaac Daniel, "Cardiac-Derived Fibroblast Growth Factor 23 Contributes To Physiologic And Pathologic Cardiac Remodeling" (2025). All ETDs from UAB. 7328.
https://digitalcommons.library.uab.edu/etd-collection/7328
