FGFR4 does not contribute to progression of chronic kidney disease

Ashlee Taylor,Melody Shi,Alexander Grabner,Tomokazu Souma,Myles Wolf,John Musgrove,Shintaro Ide,Christopher Yanucil,Christian Faul

doi:10.1038/s41598-019-50669-0

Abstract

In chronic kidney disease (CKD), elevated serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 23 have emerged as powerful risk factors for cardiovascular disease and death. Mechanistically, FGF23 can bind and activate fibroblast growth factor receptor (FGFR) 4 independently of α-klotho, the canonical co-receptor for FGF23 in the kidney, which stimulates left ventricular hypertrophy and hepatic production of inflammatory cytokines. FGF23 has also been shown to independently predict progression of renal disease, however, whether FGF23 and FGFR4 also contribute to CKD remains unknown. Here, we generated a mouse model with dual deletions of FGFR4 and α-klotho, and we induced CKD in mice with either global deletion or constitutive activation of FGFR4. We demonstrate that FGF23 is not capable of inducing phosphaturia via FGFR4 and that FGFR4 does not promote or mitigate renal injury in animal models of CKD. Taken together our results suggest FGFR4 inhibition as a safe alternative strategy to target cardiovascular disease and chronic inflammation in patients with CKD without interrupting the necessary phosphaturic effects of FGF23.

Highlights

Patients with chronic kidney disease (CKD) develop increased serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 231
Since FGF23 has been shown to activate injury-primed renal fibroblasts via FGFR4 and independent of α-klotho[13], we hypothesized that FGF23-mediated activation of FGFR4 in the kidney directly contributes to the progression of renal injury
We aimed to investigate, whether elevated FGF23 levels and klotho independent activation of FGFR4 can contribute to the pathology of kl/kl animals

Summary

Introduction

Patients with chronic kidney disease (CKD) develop increased serum levels of the phosphate regulating hormone fibroblast growth factor (FGF) 231. FGF23 has been shown to contribute to cardiovascular disease by increasing renal sodium uptake leading to volume expansion and hypertension[6]. As another potential underlying mechanism, we have previously shown that FGF23 can bind and activate FGFR4 independently of α-klotho, the canonical co-receptor of FGF23 in the kidney[7]. Since FGF23 has been shown to activate injury-primed renal fibroblasts via FGFR4 and independent of α-klotho[13], we hypothesized that FGF23-mediated activation of FGFR4 in the kidney directly contributes to the progression of renal injury

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Conclusion