Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease
Authors:
Christopher Yanucil 1, Dominik Kentrup 1 2, Isaac Campos 1, Brian Czaya 1, Kylie Heitman 1, David Westbrook 1, Gunars Osis 1,
Alexander Grabner 3, Adam R. Wende 4, Julian Vallejo 5, Michael J. Wacker 5, Jose Alberto Navarro-Garcia 6, Gema Ruiz-Hurtado 6, Fuming Zhang 7, Yuefan Song 8, Robert J. Linhardt 7 8, Kenneth White 9, Michael S. Kapiloff 10 11, Christian Faul 1
Affiliation:
1Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA
2Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, Illinois, USA
3Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
4Division of Molecular & Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
5Department of Molecular Biosciences, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
6Cardiorenal Translational Laboratory, Institute of Research, Hospital Universitario 12 de Octubre, Madrid, Spain
7Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA
8Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA
9Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
10Department of Ophthalmology, Stanford Cardiovascular Institute, Stanford University, Palo Alto, California, USA
11Department of Medicine, Stanford Cardiovascular Institute, Stanford University, Palo Alto, California, USA
Description:
Fibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that is elevated in patients with chronic kidney disease and associated with cardiovascular mortality. Experimental studies showed that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed that the complex of FGF23 and FGFR1, the physiologic FGF23 receptor in the kidney, includes soluble α-klotho (klotho) and heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether soluble klotho, a circulating protein with cardio-protective properties, and heparin, a factor that is routinely infused into patients with kidney failure during the hemodialysis procedure, regulate FGF23/FGFR4 signaling and effects in cardiac myocytes. We developed a plate-based binding assay to quantify affinities of specific FGF23/FGFR interactions and found that soluble klotho and heparin mediate FGF23 binding to distinct FGFR isoforms. Heparin specifically mediated FGF23 binding to FGFR4 and increased FGF23 stimulatory effects on hypertrophic growth and contractility in isolated cardiac myocytes. When repetitively injected into two different mouse models with elevated serum FGF23 levels, heparin aggravated cardiac hypertrophy. We also developed a novel procedure for the synthesis and purification of recombinant soluble klotho, which showed anti-hypertrophic effects in FGF23-treated cardiac myocytes. Thus, soluble klotho and heparin act as independent FGF23 co-receptors with opposite effects on the pathologic actions of FGF23, with soluble klotho reducing and heparin increasing FGF23-induced cardiac hypertrophy. Hence, whether heparin injections during hemodialysis in patients with extremely high serum FGF23 levels contribute to their high rates of cardiovascular events and mortality remains to be studied.
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