Kidney Week

Abstract: SA-PO986

Soluble Klotho Acts as a Co-Receptor for FGF23 That Interferes with FGF23’s Action on the Heart

Session Information

• Hypertension and CVD: Mechanisms - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Yanucil, Christopher, University of Alabama Birmingham, Birmingham, Alabama, United States

Christopher Yanucil,

• Richter, Beatrice, The University of Alabama at Birmingham (UAB), Birmingham, Alabama, United States

Beatrice Richter,

• Czaya, Brian A., University of Alabama at Birmingham, Birmingham, Alabama, United States

Brian A. Czaya,

• Campos, Isaac D., University of Alabama at Birmingham, Birmingham, Alabama, United States

Isaac D. Campos,

• Kentrup, Dominik Richard, University of Alabama at Birmingham, Birmingham, Alabama, United States

Dominik Richard Kentrup,

• Faul, Christian, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Christian Faul,

Background

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that increases phosphate excretion by targeting the kidney via klotho and FGF receptor (FGFR) 1. Klotho also exists in a soluble form that is released from the kidney. In patients with chronic kidney disease (CKD), changes in FGF23 and circulating sKL levels are associated with the development of cardiovascular disease and mortality. We have reported that FGF23 can contribute to cardiac hypertrophy by directly targeting cardiac myocytes via FGFR4 and inducing phospholipase Cg (PLCg) signaling. Experimental studies have shown that sKL has pleiotropic functions, including cardio-protective actions. Since a recent structural study has shown sKL acts as a scaffold to mediate FGF23-FGFR1 binding, we tested whether sKL interferes with FGF23-FGFR4 complex formation and effects in cardiac myocytes.

Methods

We purified recombinant sKL from stably transfected HEK293 cells, and determined its ability to bind recombinant FGF23 coated to a 96-well plate in the presence or absence of different FGFR isoforms. Furthermore, we co-treated neonatal rat ventricular myocytes (NRVM) with FGF23 and sKL and analyzed the activation of downstream signaling events by immunoblotting and hypertrophy via ³H-phenylalanine incorporation.

Results

sKL binds FGF23 in the absence of FGFRs and exponentially increases the affinity of FGF23 for multiple FGFR isoforms. In NRVM, co-treatment with sKL blocks FGF23-mediated PLCγ activation and stimulates Ras/MAPK signaling. Furthermore, sKL inhibits FGF23-induced hypertrophic growth of NRVM, but has no effect on FGF2-mediated hypertrophy.

Conclusion

The binding of sKL to FGF23 does not require FGFRs and might therefore act as the initial event in the formation of FGF23/sKL/FGFR signaling complexes. Similar to membrane-associated klotho, sKL increases the affinity of FGF23 for FGFR binding, and thereby causes FGF23 responsiveness of cells that express FGFRs but lack klotho. The sKL-mediated interaction between FGF23 and FGFRs appears to be more promiscuous than previously reported by not only involving FGFR1, which might explain the pleiotropic actions of sKL on various cells types. By inducing a switch in downstream signaling, sKL blocks FGF23-induced hypertrophy in cardiac myocytes and might serve as a cardio-protective therapy in CKD.

Funding

• NIDDK Support