Cell-type-specific FGF23 signalling in chronic kidney disease-associated cardiovascular injury

Abstract

Chronic kidney disease (CKD) produces a distinctive cardiovascular phenotype that traditional risk factors cannot fully explain. Fibroblast growth factor 23 (FGF23) rises early in CKD, whereas renal and circulating α-Klotho decline; this imbalance weakens canonical FGFR1c–α-Klotho signalling and permits maladaptive receptor engagement in cardiovascular tissues. The present review synthesises current evidence on cell-type-specific FGF23 signalling in CKD, focusing on receptor topology, intracellular signalling cascades, and therapeutic implications. In vascular endothelial cells, excess FGF23 promotes oxidative stress, depletes nitric oxide, and impairs endothelial function, partly through FGFR1–PLCγ2–NOX2-dependent generation of reactive oxygen species. In vascular smooth muscle cells, FGF23 intersects with MEK–ERK signalling and phosphate sensing, although medial calcification is driven predominantly by phosphate retention and α-Klotho deficiency rather than by FGF23 alone. In cardiomyocytes, α-Klotho-independent FGFR4 signalling activates the PLCγ–calcineurin–NFAT axis, promoting left ventricular hypertrophy, calcium-handling abnormalities, and arrhythmogenic vulnerability. FGF23 also contributes to cardiac fibroblast activation and extracellular-matrix remodelling. A parallel, largely FGF23-independent calcium-sensing receptor–calcium–organelle stress pathway may additionally amplify mitochondrial injury, cGAS–STING signalling, and inflammasome-mediated cell death within the CKD–mineral bone disorder (CKD-MBD) milieu. Emerging experimental evidence that skeletal muscle can generate FGF23 during phosphate stress broadens the traditional bone-centred model of CKD-MBD. Calciprotein particles are additionally implicated as an extracellular signal coupling mineral loading to FGF23 secretion, and prognostic data from naturally occurring feline CKD support a conserved clinical relevance across species. Current therapies lower FGF23 only indirectly, through phosphate, parathyroid hormone, iron, and kidney-protective pathways, and dedicated cardiovascular outcome trials targeting the FGF23–α-Klotho axis are still lacking.