Soluble klotho and heparin modulate the pathologic cardiac actions of FGF23 in chronic kidney disease

Authors
Yanucil, C.
Kentrup, D.
Campos, I.
Czaya, B.
Heitman, K.
Westbrook, D.
Osis, G.
Grabner, A.
Wende, A.R.
Vallejo, J.
ORCID
https://orcid.org/0000-0003-2219-5833
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Issue Date
2022
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Terms of Use
Attribution-NonCommercial-NoDerivs 3.0 United States
CC BY-NC-ND : this license allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
Full Citation
Soluble klotho and heparin modulate the pathologic cardiac actions of FGF23 in chronic kidney disease, C. Yanucil, D. Kentrup, I. Campos, B. Czaya, K. Heitman, D. Westbrook, G. Osis, A. Grabner, A. R. Wende, J. Vallejo, M. Wacker, J. Alberto Navarro-Garcia, G. Ruiz-Hurtado, F. Zhang, Y. Song, R. J. Linhardt, K. White, M. Kapiloff, C. Faul, Kidney International, in press, 2022.
Abstract
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.
Description
Kidney International, in press
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
Publisher
Elsevier
Relationships
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
https://harc.rpi.edu/
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A full text version is available in DSpace@RPI
Open Access
A full text version is available in DSpace@RPI