Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome

Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. 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. A mouse model of CRS was created by surgical myocardial infarction for 12 weeks. CRS mice showed a significant increase of circulatory and renal FGF23 protein levels, as well as an upregulation of p-GSK, active-beta-catenin, TGF-beta, collagen I and vimentin, a 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 FGF receptor blocker PD173074 or beta-catenin blocker IGC001. In fibroblasts (NRK-49F), expression of FGFR4 rather than Klotho was detected. Recombinant FGF23 upregulated the expression of p-GSK, active-beta-catenin, TGF-beta, collagen I and vimentin proteins. These changes were attenuated by FGFR4 blockade with BLU9931 or beta-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/beta-catenin signaling pathway.

Automated summary

The study found that FGF23 plays an important role in CRS-induced renal fibrosis by partly activating the FGFR4/beta-catenin signaling pathway.