Identification of the cardiac FGF23 receptor and distinguishing its role in cardiorenal syndrome and Congestive Heart Failure

• Applicant: Dr. Alexander Grabner
• Subject Area: Nephrology
• Term: from 2012 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 222738104

Chronic kidney disease (CKD), which affects 10-13% of the European population, is a public health epidemic that increases risk of death due to cardiovascular disease (CVD). Left ventricular hypertrophy (LVH) is an important mechanism of CVD and affects up to 90% of CKD patients. Fibroblast growth factor 23 (FGF23) is a hormone that regulates phosphate metabolism and its levels are constitutively elevated in CKD. Recent human studies demonstrated a dose-dependent association between increasing FGF23 levels and greater risk of mortality. A plausible mechanism for this was offered by clinical studies that showed an association between elevated FGF23 levels and an increased prevalence of LVH. Nevertheless, it remained unclear whether FGF23 contributes directly to CVD or is simply a biomarker of toxicity. Recently, the group of Dr. Faul has demonstrated that FGF23 causes hypertrophy of cardiocytes in vitro and severe LVH in three animal models with increased serum FGF23 levels, indicating that pathological cardiac effects can be directly attributed to FGF23. In the proposed research project, we will focus on the identification of the cardiac FGF23 receptor. Our preliminary data indicate that FGF23 activates FGF receptors (FGFR) on cardiocytes, thereby inducing pro-hypertrophic signaling pathways. First mapping experiments indicate that FGFR4 is specifically involved in this process. We will continue to characterize the precise FGFR isoform(s) by generating two transgenic animal models: the first will constitutively activate FGFR signaling, while the second will deplete the FGFR responsible for FGF23-induced hypertrophic growth. If high FGF23 levels will be shown to be a direct cause of LVH, it would strengthen the justification for FGF23 reduction in clinical practice in an effort to reduce LVH and improve survival of CKD patients. Furthermore, our analysis of the cardiac FGF23 receptor might serve as a novel drug target for pharmacological intervention of LVH in CKD.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Christian Faul