Abstract: SA-PO989
FGF23 Contributes to Cardiac Fibrosis in CKD
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
- Richter, Beatrice, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Yanucil, Christopher, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Czaya, Brian A., The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Campos, Isaac D., The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Kentrup, Dominik Richard, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Faul, Christian, The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background
The risk for cardiovascular diseases is enormously increased in patients with chronic kidney disease (CKD). Over 90% of patients with end-stage renal disease develop pathologic cardiac remodeling, including hypertrophy and fibrosis that can lead to heart failure. Fibroblast growth factor (FGF) 23 is a bone-derived hormone that increases phosphate excretion by targeting the kidney via FGF receptor (FGFR) 1 and klotho. In early stages of CKD, serum FGF23 levels increase to compensate the rise in serum phosphate concentrations. High FGF23 concentrations are associated with the development of cardiovascular disease and a strong predictor for mortality in CKD. Our previous studies in rodents have shown that FGF23 can directly target the heart and contribute to cardiac hypertrophy. FGF23 binds to FGFR4 on cardiac myocytes in a klotho-independent manner, leading to the activation of a pro-hypertrophic signaling cascade, including phospholipase Cγ (PLCγ) and calcineurin. Since in animal models with elevated serum FGF23 levels cardiac hypertrophy is accompanied by fibrosis, we wanted to test if FGF23 can also directly target cardiac fibroblasts, using isolated primary cell culture models.
Methods
We have established primary cardiac fibroblast cultures from newborn rats, as well as adult mice and rats, and we analyze expression levels of different FGFR isoforms and klotho by qPCR. We treat cells with increasing FGF23 concentrations and investigate the activation of FGFRs, downstream signal mediators and pro-fibrotic gene programs by qPCR, immunoblotting and enzymatic assays. Furthermore, we study cell proliferation, migration and survival. We determine if co-treatment with inhibitors against FGFRs, PLCγ or calcineurin blocks FGF23-mediated effects on fibroblasts.
Results
Cardiac fibroblasts isolated from mice and rats express high levels of FGFR1 and to a lower extent also FGFR4. FGF23 promotes proliferation, migration and activation of fibroblasts when compared to vehicle-treated control cells.
Conclusion
We postulate that FGF23 contributes to pathologic cardiac remodeling by directly targeting different cell types in the myocardium, i.e. cardiac myocytes via FGFR4 and cardiac fibroblasts via FGFR1. Pharmacological blockade of FGFRs might serve as novel cardio-protective therapy in CKD.
Funding
- Government Support - Non-U.S.