Role of FGF23 and Phosphate in Chronic Kidney Disease

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PROJECT SUMMARY In chronic kidney disease (CKD), hyperphosphatemia and increased fibroblast growth factor 23 (FGF23) levels are associated with faster CKD progression, cardiovascular events and death. Novel therapeutic approaches to limit the effects of excess FGF23 and phosphate (Pi), slow CKD progression and prevent adverse outcomes are desperately needed. In preliminary data for this project, chronic administration of FGF23 or dietary Pi supplementation that further increased FGF23 levels in mice with CKD, accelerate CKD progression. In addition, we show that FGF23 and Pi are powerful regulators of circadian rhythms in the kidney. Impaired circadian rhythms, or chronodisruption, is an established feature of CKD, but the factors contributing to altered expression of kidney clock genes, and the consequences on kidney function and mortality remain unclear. FGF23 and Pi activate FGF receptor 1 (FGFR1), increase early growth response protein 1 (EGR1) activation and stimulate nuclear factor κB (NFκB), an established inhibitor of the repressor arm of the core molecular clock. We show that administration of an FGFR1 inhibitor in FGF23-treated kidney cells and in mice with CKD reduces EGR1 expression and corrects the expression of clock genes in the kidney. Importantly, we show that FGFR1 inhibitor improved kidney function in mice with CKD. In this innovative proposal, we will test the hypothesis that increased FGF23 and Pi accelerate CKD progression through disruption of the kidney circadian clock, and that this process is mediated by FGFR1. In Aim 1, we will define the combined and individual roles of FGF23 and Pi on kidney function and identify their kidney-specific molecular targets. We will use low and high dietary Pi administration, FGF23 administration and bone-specific Fgf23 deletion in the wild-type (WT) and Col4a3KO mouse model of progressive CKD. In Aim 2, we will assess the role of EGR1 and NFκB in mediating the effects of FGF23 and Pi on the kidney molecular clock. We will use genetic and pharmacological approaches to modulate EGR1 and NFκB signaling, and assess transcriptional oscillations of kidney clock genes in models of acute and chronic FGF23 and Pi excess. We will identify kidney-specific gene targets using EGR1 and NFκB ChIP sequencing. In Aim 3, we will demonstrate the contribution of increased Bmal1, one of the main core clock activators, to impaired kidney function using genetic approaches to lower kidney Bmal1 expression in WT and Co4a3KO mice. We will also use genetic and pharmacologic blockade of FGFR1 in mice with CKD to demonstrate its therapeutic potential to prevent FGF23 and Pi induced inflammation on the kidney and restore kidney circadian rhythms. We will assess amelioration of lifespan, markers of mineral metabolism and kidney morphology and function. These innovative aims are supported by a productive collaborative team with expertise, skills and resources at Northwestern University that will further develop our understanding of FGF23 and Pi function, and support our ultimate goal of developing novel therapies to improve CKD-associated outcomes.