Fibroblast Growth Factor 23 Directly Contributes to CKD Progression in Col4a3 Knockout Mice

Background: Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced mainly by osteocytes. Increased levels of FGF23 are associated with increased mortality in CKD. Whether FGF23 has a direct role on CKD progression is unclear. In this study we tested the hypothesis that increased FGF23 levels accelerate CKD progression independently of phosphate. Methods: First, we fed adult wild-type (WT) and Col4a3KO male mice, an established model of progressive CKD, diets containing either 0.7% Pi (normal Pi, NP) or 2% Pi (high Pi, HP) continuously from 12 weeks of age to show the combined effects of FGF23 and Pi on CKD progression. Next, to separate the effects of FGF23 from hyperphosphatemia we deleted Fgf23 in the bone (Osx-cre) of WT (Fgf23cKO) and Col4a3KO (Col4a3KO/Fgf23cKO) mice fed a NP diet. In all mice, we assessed lifespan, kidney function and markers of mineral metabolism. Results: Compared to NP-WT mice, dietary Pi supplementation increased circulating FGF23 and PTH levels, resulting in increased urinary Pi excretion and reduced serum Pi levels in HP-WT. NP-Col4a3KO mice with advanced CKD showed increased BUN, serum creatinine, FGF23, and PTH levels, late onset hyperphosphatemia, and a reduced lifespan compared to NP-WT mice. Dietary Pi supplementation in Col4a3KO mice further increased serum creatinine, FGF23 and PTH levels, and led to earlier onset of hyperphosphatemia. As a result, HP-Col4a3KO died on average 2.5 weeks earlier than NP-Col4a3KO mice. In contrast, Fgf23 deletion in WT mice slightly reduced FGF23 and increased serum Pi levels. In Col4a3KO mice with CKD, Fgf23 deletion corrected FGF23 levels by 60%, did not impact PTH levels, and further increased hyperphosphatemia. Despite further increases in Pi levels, BUN and serum creatinine levels were unchanged, and Col4a3KO/Fgf23cKO mice lived on average 2 weeks longer than Col4a3KO mice. Conclusion: In aggregate, FGF23 excess and hyperphosphatemia accelerated CKD progression whereas FGF23 reduction improved survival despite persistent hyperphosphatemia and hyperparathyroidism. This suggests that increased FGF23 in CKD directly contributes to CKD progression. Funding: NIDDK Support