Role of FGF23 and Phosphate in Chronic Kidney Disease

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 slow CKD progression and prevent adverse outcomes in CKD are desperately needed but current therapies are suboptimal. In mice with CKD, we show that dietary phosphate (Pi) supplementation that lead to further increase in FGF23 levels or chronic administration of FGF23 alone accelerate CKD progression. We also show that FGF23 and Pi activate FGF receptor 1 (FGFR1) signaling and are powerful regulators of circadian rhythms in the kidney of healthy mice and mice with CKD. Altered circadian rhythms, or chronodisruption, is a long-recognized key feature of CKD contributing to circadian changes in blood pressure, and to altered expression of kidney clock genes. EGR1 is a downstream effector of FGFR1 that stimulates NFκβ-mediated inflammation. NFκβ is 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 rescues altered expression of clock genes in the kidney. Importantly, we show that FGFR1 inhibitor also improved kidney function in mice with CKD. In this innovative proposal, we will test the hypothesis that increased FGF23 and Pi levels 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 NFκβ in mediating the effects of FGF23 and Pi on the kidney molecular clock. We will use genetic deletion of Egr1 and Ikkβ and pharmacological inhibition of NFκβ, 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 NFκβ ChIPseq. In Aim 3, we will demonstrate the contribution of increased Bmal1 to impaired kidney function using genetic approaches to lower kidney Bmal1 expression in WT and Co4a3KO mice. We will also use genetic deletion and pharmacologic inhibition of FGFR1 in mice with CKD to demonstrate the therapeutic potential of FGFR1 inhibition 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.