Changes in phosphate metabolism cause pathologic cardiac remodeling in chronic kidney disease (CKD)

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ABSTRACT Fibroblast growth factor (FGF) 23 is a bone-derived hormone that targets the kidney via FGF receptors (FGFR) and klotho, a transmembrane protein (‘mKL’) that acts as an FGF23 co-receptor, thereby increasing renal phosphate excretion and lowering serum phosphate levels. In patients with chronic kidney disease (CKD), FGF23-responsiveness and phosphate reabsorption are impaired, leading to increased serum phosphate concentrations and FGF23 production in bone. Clinical studies have shown that elevated serum FGF23 levels are strongly associated with negative outcomes in CKD, such as cardiac hypertrophy and cardiovascular mortality. 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 C (PLC)/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 that is not expressed in the heart. Klotho also exists in a truncated soluble form (‘sKL’) that is generated by proteolysis of mKL and released from the kidney. Experimental studies indicate that sKL has tissue-protective effects, including anti-hypertrophic and anti-fibrotic actions in the heart, similar to active vitamin D (‘1,25D‘), which also acts as a cardio-protective hormone. In patients with CKD, serum levels of sKL and 1,25D are significantly reduced, and it is thought that a loss of sKL’s and 1,25D’s protective effects contributes to CKD-associated tissue injury. Since our published and preliminary work indicates that sKL and 1,25D can inhibit FGF23-induced signaling and hypertrophy in cultured cardiac myocytes, we hypothesize that sKL and 1,25D attenuate pathologic actions of FGF23 in the heart. In Aim 1, we will study in mice on an adenine-rich diet (AD), a model for CKD with high FGF23 that develops cardiac hypertrophy, whether systemic sKL elevations by AAV delivery attenuate cardiac hypertrophy, and vise-versa, whether the absence of sKL in a mouse model with kidney-specific klotho deletion accelartes cardiac injury. In isolated cardiac myocytes, we will study the mechanism underlying sKL’s anti- hypertrophic effects and determine if by interacting with FGF23, sKL can block FGF23 binding to FGFR4 and/or FGFR4 activation. In Aim 2, we will determine if administration of 1,25D has cardio-protective effects in mice on AD, as well as in genetically modified mice with constitutive FGFR4 activation and cardiac hypertrophy. We will also study if in mice with cardiac-specific deletion of the vitamin receptor (VDR) which spontaneously develop cardiac hypertrophy, the elevation of serum FGF23 levels by AD or by osmotic minipump infusions of recombinant FGF23 aggravates cardiac injury. We postulate that via the studied mechanism, elevated serum FGF23, and reduced serum levels of sKL and 1,25D, three clinical hallmarks of CKD, synergistically contribute to CKD-associated cardiac injury. A combination of pharmacological interventions activating VDR, elevating circulating sKL and blocking FGF23/FGFR4 signaling might have cardio-protective effects in patients with CKD.