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

Abstract

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.