Abstract
Over one in ten adults manifests physiological evidence of chronic kidney disease (CKD), which significantly reduces life expectancy due to cardiovascular complications. Left ventricular hypertrophy (LVH) is at the center of this relationship and up to 90% of patients with CKD also manifest LVH. Fibroblast growth factor (FGF) 23 is a phosphorus-regulating hormone responsible for maintaining normal serum phosphate levels in early stages of CKD; furthermore, FGF23 levels rise during the course of the disease and correlate with the CKD stage. High plasma FGF23 levels are independently associated with elevated left ventricular mass, LVH and increased risk of mortality. These correlative data suggest a direct role of FGF23 in the pathogenesis of cardiovascular disease; however, a direct causal mechanism of FGF23-induced LVH and subsequent death has yet to be demonstrated. This thesis project explores the direct effects of FGF23 on the heart. Our results indicate that FGF23 can activate pro-hypertrophic gene programs, elevate the expression levels of sarcomeric proteins and cause an increase in cardiac myocyte surface area. Cardiac elevation of FGF23 levels via intramyocardial injection induce hypertrophy in vivo. Furthermore, systemic elevation of serum FGF23 levels in mice via tail-vein injections results in a hypertrophic cardiac phenotype when compared to PBS-injected control animals. We show that FGF23- mediated signaling in cardiac myocytes occurs in an FGF receptor-dependent manner, but in the absence of klotho, a previously described co-receptor required for FGF23’s biological effects in the kidney and parathyroid glands. Homozygous klotho-ablated mice, which have a greater than 15-fold increase in serum FGF23 levels compared to wild-type littermate controls, develop LVH. Interestingly, heterozygous klotho-ablated mice display a 4-fold increase in serum FGF23 and subsequently develop a moderate cardiac hypertrophic phenotype. Serum FGF23 levels are 12-fold increased in 5/6 nephrectomized rats compared to sham controls, and treatment with a pan-FGF receptor inhibitor attenuates LVH despite no change in blood pressure or kidney parameters. In dissecting the pathways responsible for FGF23-induced cardiac hypertrophy, our results indicate that the effect of FGF23 on cardiac myocytes is largely mediated through a calcineurin-dependent pathway, ultimately resulting in the activation of nuclear factor of activated T cells (NFAT). Our future research endeavors will continue to focus on the signaling events responsible for FGF23-mediated hypertrophy, with the ultimate goal of identifying the cardiac FGF23 receptor(s) involved in initiating this pro-hypertrophic signaling cascade and suggesting a plausible therapeutic intervention for preventing the high rates of LVH found in the CKD population.