Christian Faul Pilot

点击翻译按钮获取中文摘要

Pilot Awardee #2: Faul, Christian H., PhD Title: FGF23 Contributes to Systemic Inflammation and Cardiac Injury in Animal Models of AKI AKI is associated with increased risk of in-hospital mortality, and confers greater risks of developing CKD, ESRD, and death long after the initial AKI episode has resolved. Early elevations in circulating levels of the osteocyte-derived phosphaturic hormone, fibroblast growth factor (FGF) 23, are strongly associated with adverse outcomes in patients with AKI. A rapid, early increase in serum FGF23 levels has been also reported in two mouse models of toxin-induced AKI (i.e. administration of folic acid and pigment nephropathy). Although increased production rather than decreased elimination seems to account for elevated FGF23 levels in AKI, the source and mechanism of FGF23 synthesis and secretion in AKI is not understood, but appears to occur independently of established regulators of FGF23 production, such as elevated serum phosphate. FGF23 targets the kidney via FGF receptors (FGFR) and klotho, a transmembrane protein that acts as an FGF23 co-receptor, thereby increasing renal phosphate excretion and lowering serum phosphate levels. In patients with CKD, FGF23-responsiveness and phosphate reabsorption are impaired due to a loss of functional kidney mass and reduced klotho expression, leading to increased serum phosphate concentrations and FGF23 production in bone. Clinical CKD studies have shown that elevated serum FGF23 levels are strongly associated with negative outcomes, such as cardiac hypertrophy and cardiovascular mortality. FGF23 is also strongly associated with higher levels of inflammatory markers in CKD patients. Our translational work indicates that circulating FGF23 can directly contribute to tissue injury that is associated with CKD. By activating FGF receptor (FGFR) 4 and subsequent phospholipase Cγ (PLCγ/calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, FGF23 induces cardiac hypertrophy and fibrosis in rodents. This pathologic effect occurs independently of klotho. Furthermore, we have shown that by activating FGFR4/PLCγ/calcineurin/NFAT signaling in hepatocytes, FGF23 increases the production of C-reactive protein (CRP) and interleukin 6 (IL6), and animal models with CKD and elevated FGF23 show higher levels of CRP and IL6 in liver and blood.