FGF23 Promotes Renal Fibrosis Independently Of Klotho In Mice With Cardiorenal Syndrome

Background and Objective:Rationale Cardiorenal syndrome(CRS)has a high mortality,but its pathogenesis remains elusive.Fibroblast growth factor 23(FGF23)is a newly discovered endocrine hormone produced by osteoblasts/osteocytes in bone that acts on the kidney and parathyroid glands to regulate phosphate homeostasis and vitamin D metabolism.FGF23 is increased in both renal dysfunction and cardiac dysfunction,and FGF receptor 4(FGFR4)has been identified as a receptor for FGF23.Recently,FGF23 has been reported to induce left ventricular hypertrophy and promotes myocardial fibrosis,which is associated with the activation of calcineurin/NFAT signal pathway.Deficiency of FGF23 causes growth retardation and shortens the lifespan,but it is unclear whether excess FGF23 is detrimental in CRS.This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis.Methods:A mouse model of CRS was created by surgical myocardial infarction(MI)for 6 wks.Then the effects of FGF23 on cardiorenal dysfunction,renal fibrosis,and fibrosis-related signaling pathways were examined by intramyocardial injection of an FGF23-overexpressing adeno-associated virus and by administration of an FGF23 receptor antagonist PD 173074.The effect of FGF23 recombinant protein stimulation for 24 hours on NRK-49F cells,the expression levels of fibrosis-related gene and protein were detected by real time PCR and Western blot.Results:CRS mice showed a significant increase of plasma and renal FGF23 levels,as well as upregulation of FGFR4,β-catenin,TGF-β,type Ⅰ collagen,and vimentin,downregulation of renal Klotho expression,and induction of cardiorenal dysfunction and cardiorenal fibrosis.These changes were enhanced by cardiac overexpression of FGF23 and attenuated by FGF23 receptor blockade with PD 173074.In cultured renal fibroblasts(NRK-49F cells),expression of FGFR4 was detected,but not Klotho expression.Recombinant FGF23 promoted the proliferation of these cells and upregulated the expression of β-catenin,TGF-β,type Ⅰ collagen,and vimentin proteins.Conclusion:FGF23 promotes CRS-induced renal fibrosis mediated by β-catenin and TGF-P in a Klotho independent manner.