The renal response to FGF23 shifts from phosphaturia toward inflammation in kidney disease.

FGF23 excess is associated with morbidity and mortality, but the role of excessive circulating FGF23 concentrations as a causative factor of pathology is controversial. Here, we investigated the consequences of FGF23 excess in kidney disease. This study used three disease models: anti-glomerular basement membrane (anti-GBM) disease, Adriamycin nephropathy, and adenine-containing diets. Anti-GBM and Adriamycin mice and matched control mice received recombinant FGF23 (1 µg) or vehicle for six days (anti-GBM) or once (Adriamycin model), with dissection 24 h after the last injection. We established precision-cut kidney slices (PCKS) in adenine nephropathy for 24 h of treatment with recombinant FGF23 or vehicle. We assessed serum cytokines, biochemistry, and renal transcriptomes and histology of mice and patients with IgA nephropathy. RNA-Seq data and published transcriptomes underwent gene set enrichment, bulk ligand-receptor interaction analysis, and cell-type decomposition. Experimental anti-GBM disease caused decreased glomerular filtration rate, albuminuria, and renal tubular casts. FGF23 treatment increased phosphaturia and circulating soluble tumor necrosis factor receptor 1. The anti-GBM model showed FGF23-driven proinflammatory transcriptional signatures and Vcam1, Pdgfrb, and chemokine signaling, which were absent in FGF23-treated healthy mice. FGF23 increased renal macrophage content by transcriptome deconvolution and by immunofluorescence. In Adriamycin-induced nephropathy and in PCKS from adenine nephropathy, short-term FGF23 excess increased proinflammatory transcripts. Human data revealed associations between circulating FGF23 and renal immune cell infiltration. We found FGF23-driven renal patterns of proinflammatory gene and protein expression or leukocyte overabundance. The present data provide evidence that excess FGF23 directly drives inflammation in kidney disease and may serve as a therapeutic target.