Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

Christopher Yanucil; Dominik Kentrup; Isaac Campos; Brian Czaya; Kylie Heitman; David Westbrook; Gunars Osis; Alexander Grabner; Adam R. Wende; Julian Vallejo; Michael J. Wacker; Jose Alberto Navarro-Garcia; Gema Ruiz-Hurtado; Fuming Zhang; Yuefan Song; Robert J. Linhardt; Kenneth White; Michael S. Kapiloff; Christian Faul

doi:10.1016/j.kint.2022.03.028

Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

Christopher Yanucil, Dominik Kentrup, Isaac Campos, Brian Czaya, Kylie Heitman, David Westbrook, Gunars Osis, Alexander Grabner, Adam R. Wende, Julian Vallejo, Michael J. Wacker, Jose Alberto Navarro-Garcia, Gema Ruiz-Hurtado, Fuming Zhang, Yuefan Song, Robert J. Linhardt, Kenneth White, Michael S. Kapiloff, Christian Faul^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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.

Original language	English (US)
Pages (from-to)	261-279
Number of pages	19
Journal	Kidney international
Volume	102
Issue number	2
DOIs	https://doi.org/10.1016/j.kint.2022.03.028
State	Published - Aug 2022

Funding

This study was supported by the Deutsche Forschungsgemeinschaft (DK), the National Science Foundation (IC), the American Society of Nephrology (AG), the American Heart Association (GO), and by the National Institutes of Health (grants F31DK115074 [CY], F31DK117550 [BC], P01AG039355 [MJW], P01AG039355-08S2 [MJW and JV], R01HL133011 [ARW], R01HL146111 [MK], R01HL128714 [CF], and R01HL145528 [KW and CF]). RJL was supported by GlycoMIP, a National Science Foundation Materials Innovation Platform funded through Cooperative Agreement DMR-1933525. GR-H was supported by the Instituto de Salud Carlos III cofunded by the European Regional Development Fund (Fondos FEDER, CP15/00129 and PI17/01093) and Fundaci\u00F3n Renal \u00CD\u00F1igo \u00C1lvarez de Toledo (FRIAT). CF was supported by the UAB-UCSD O'Brien Core Center for Acute Kidney Injury Research, the AMC21 program of the Department of Medicine at UAB, and the Tolwani Innovation Award from the Division of Nephrology at UAB. CF has served as a consultant for Bayer and Calico Labs. CY and CF are inventors of 2 pending patents (PCT/US2019/049211 and PCT/US19/49161) aimed to produce and detect bioactive soluble klotho, and they are cofounders of a startup biotech company (Alpha Young LLC) that has the goal to further develop and commercialize these products and assays. CF is currently the CSO of Alpha Young LLC. CF has a patent on fibroblast growth factor receptor inhibition (European Patent No. 2723391). KW received royalties from Kyowa-Hakko-Kirin Pharmaceutics and research funding from Akebia/Keryx and Calico Labs. All the other authors declared no competing interests. This study was supported by the Deutsche Forschungsgemeinschaft (DK), the National Science Foundation (IC), the American Society of Nephrology (AG), the American Heart Association (GO), and by the National Institutes of Health (grants F31DK115074 [CY], F31DK117550 [BC], P01AG039355 [MJW], P01AG039355-08S2 [MJW and JV], R01HL133011 [ARW], R01HL146111 [MK], R01HL128714 [CF], and R01HL145528 [KW and CF]). RJL was supported by GlycoMIP, a National Science Foundation Materials Innovation Platform funded through Cooperative Agreement DMR-1933525. GR-H was supported by the Instituto de Salud Carlos III cofunded by the European Regional Development Fund (Fondos FEDER, CP15/00129 and PI17/01093) and Fundaci\u00F3n Renal \u00CD\u00F1igo \u00C1lvarez de Toledo (FRIAT). CF was supported by the UAB-UCSD O\u2019Brien Core Center for Acute Kidney Injury Research, the AMC21 program of the Department of Medicine at UAB, and the Tolwani Innovation Award from the Division of Nephrology at UAB.

Keywords

cardiac hypertrophy
chronic kidney disease
fibroblast growth factor 23
heparin
klotho
phosphate metabolism

ASJC Scopus subject areas

Nephrology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.kint.2022.03.028

Cite this

Yanucil, C., Kentrup, D., Campos, I., Czaya, B., Heitman, K., Westbrook, D., Osis, G., Grabner, A., Wende, A. R., Vallejo, J., Wacker, M. J., Navarro-Garcia, J. A., Ruiz-Hurtado, G., Zhang, F., Song, Y., Linhardt, R. J., White, K., Kapiloff, M. S., & Faul, C. (2022). Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease. Kidney international, 102(2), 261-279. https://doi.org/10.1016/j.kint.2022.03.028

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title = "Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease",

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.",

keywords = "cardiac hypertrophy, chronic kidney disease, fibroblast growth factor 23, heparin, klotho, phosphate metabolism",

author = "Christopher Yanucil and Dominik Kentrup and Isaac Campos and Brian Czaya and Kylie Heitman and David Westbrook and Gunars Osis and Alexander Grabner and Wende, {Adam R.} and Julian Vallejo and Wacker, {Michael J.} and Navarro-Garcia, {Jose Alberto} and Gema Ruiz-Hurtado and Fuming Zhang and Yuefan Song and Linhardt, {Robert J.} and Kenneth White and Kapiloff, {Michael S.} and Christian Faul",

note = "Publisher Copyright: {\textcopyright} 2022 International Society of Nephrology",

year = "2022",

month = aug,

doi = "10.1016/j.kint.2022.03.028",

language = "English (US)",

volume = "102",

pages = "261--279",

journal = "Kidney international",

issn = "0085-2538",

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Yanucil, C, Kentrup, D, Campos, I, Czaya, B, Heitman, K, Westbrook, D, Osis, G, Grabner, A, Wende, AR, Vallejo, J, Wacker, MJ, Navarro-Garcia, JA, Ruiz-Hurtado, G, Zhang, F, Song, Y, Linhardt, RJ, White, K, Kapiloff, MS & Faul, C 2022, 'Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease', Kidney international, vol. 102, no. 2, pp. 261-279. https://doi.org/10.1016/j.kint.2022.03.028

TY - JOUR

T1 - Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

AU - Yanucil, Christopher

AU - Kentrup, Dominik

AU - Campos, Isaac

AU - Czaya, Brian

AU - Heitman, Kylie

AU - Westbrook, David

AU - Osis, Gunars

AU - Grabner, Alexander

AU - Wende, Adam R.

AU - Vallejo, Julian

AU - Wacker, Michael J.

AU - Navarro-Garcia, Jose Alberto

AU - Ruiz-Hurtado, Gema

AU - Zhang, Fuming

AU - Song, Yuefan

AU - Linhardt, Robert J.

AU - White, Kenneth

AU - Kapiloff, Michael S.

AU - Faul, Christian

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - cardiac hypertrophy

KW - chronic kidney disease

KW - fibroblast growth factor 23

KW - heparin

KW - klotho

KW - phosphate metabolism

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M3 - Article

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AN - SCOPUS:85130882416

SN - 0085-2538

VL - 102

SP - 261

EP - 279

JO - Kidney international

JF - Kidney international

IS - 2

ER -

Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

Abstract

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UN SDGs

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