Abstract: SA-PO771
Heparin Infusions Contribute to Cardiovascular Damage in CKD by Promoting Pathologic Effects of FGF-23
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Yanucil, Christopher, University of Alabama, Birmingham, Alabama, United States
- Kentrup, Dominik, University of Alabama, Birmingham, Alabama, United States
- Campos, Isaac D., University of Alabama, Birmingham, Alabama, United States
- Richter, Beatrice, University of Alabama, Birmingham, Alabama, United States
- Czaya, Brian A., University of Alabama, Birmingham, Alabama, United States
- Heitman, Kylie, University of Alabama, Birmingham, Alabama, United States
- Faul, Christian, University of Alabama, Birmingham, Alabama, United States
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. Most FGF family members interact with heparin as a co-factor for efficient FGFR activation. Endocrine FGFs, such as FGF23, have reduced heparin binding affinity and instead require the transmembrane protein klotho as FGFR co-receptor. Patients on hemodialysis (HD) have extremely high serum FGF23 levels and receive high amounts of heparin to prevent blood clotting. We have shown that FGF23 causes cardiac hypertrophy by directly targeting cardiac myocytes via FGFR4 in the absence of klotho, and here we test whether heparin affects this pathologic process.
Methods
We have developed a multi-well assay to measure FGFR binding affinities of FGF23 and test effects of heparin co-incubations. We co-treat cultured cardiac myocytes with FGF23 and heparin and analyze changes in signaling events and in cell area as a readout for hypertrophy. Finally, mimicking a HD-like administration pattern, we inject heparin via the tail vein into two mouse models of FGF23 elevation, i.e. adenine diet-induced kidney failure and repetitive injections of recombinant FGF23.
Results
While purified FGF23 and FGFR4 proteins show only a weak interaction, co-incubation with patient grade heparin increases their binding affinity 10-fold. Heparin increases FGF23-induced signaling and hypertrophic growth of cardiac myocytes. Both mouse models with elevated serum FGF23 levels show increased cardiac hypertrophy when heparin is administered.
Conclusion
We show that heparin can increase the FGFR binding affinity and cellular effects of FGF23. Specifically, heparin aggravates the klotho-independent FGFR4-mediated actions of FGF23 on cardiac myocytes and thereby cardiac injury in mice with systemic FGF23 elevations. Our experiments suggest that in HD patients, administered heparin acts as a biologically active, circulating co-receptor for FGF23 that increases FGF23 affinity for FGFR4 thereby aggravating the pathologic actions of FGF23 on the heart and contributing to the increased cardiovascular mortality.
Funding
- NIDDK Support