Identification of the cardiac FGF23 receptor and distinguishing its role in cardiorenal syndrome and Congestive Heart Failure
Final Report Abstract
Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in CKD and affects up to 90% of patients by the time they reach dialysis. Fibroblast growth factor (FGF) 23 is a hormone that regulates phosphate metabolism and its levels are constitutively elevated in CKD and continuously rise as patients progress to renal failure. While this massive increase in FGF23 helps to maintain normal serum phosphate levels, human studies demonstrated a dosedependent association between FGF23 levels, increased prevalence of LVH and greater risk of mortality among CKD patients. Recently, FGF23 has been shown to directly cause hypertrophic growth of isolated cardiac myocytes and severe LVH in animal models with increased serum FGF23. This effect is mediated by FGF receptors (FGFR) but does not require klotho, the FGF23 coreceptor in “classic” FGF23 target organs like the kidney. In this study we demonstrate, that FGF23 directly activates FGFR4 in vitro. Binding to FGFR4 in the absence of Klotho leads to activation of downstream signaling events involving the PLCγ/calcineurin/NFAT pathway. Furthermore, an isoform-specific FGFR4 blocking antibody inhibits FGF23-induced hypertrophic growth of cardiac myocytes in vitro, and attenuates LVH in the 5/6 nephrectomy rat model of CKD without reducing the animals' elevated blood pressure or FGF23 levels. Experimental elevation of FGF23 in FGFR4 knockout mice does not cause LVH, and isolated cardiac myocytes from these mice are protected from FGF23- induced hypertrophy. Finally, a FGFR4 knockin mouse model carrying a gain-of-function mutation (G385R) spontaneously develops LVH in the absence of FGF23 elevations. These data indicate that FGF23-mediated FGFR4 activation causes LVH in rodents and that FGFR4 blockade might serve as a novel pharmacological intervention for LVH in CKD. Since FGFR4 activation per se seems to be sufficient to induce LVH, we postulate that FGFR4 is part of a novel pro-hypertrophic signaling pathway in the heart that could also be activated in patients with primary cardiomyopathies.
