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

• DOI: 10.1016/j.kint.2022.03.028
• Publication Date: 2022-05-02T14:53:34Z
• Authors: 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 Nava...; Gema Ruiz-Hurtado; Fuming Zhang; Yuefan Song; Robert J. Linhardt; Kenneth White; Michael S. Kapiloff; Christian Faul
• Keywords: Klotho

Fibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that elevated in patients with chronic kidney disease and associated cardiovascular mortality. Experimental studies showed FGF23 levels induce cardiac hypertrophy by targeting myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed the complex of FGFR1, physiologic kidney, includes soluble α-klotho (klotho) heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether klotho, circulating protein cardio-protective properties, routinely infused into failure during hemodialysis procedure, regulate FGF23/FGFR4 signaling effects myocytes. We developed plate-based binding assay to quantify affinities specific FGF23/FGFR interactions found klotho heparin mediate distinct FGFR isoforms. Heparin specifically mediated FGFR4 increased stimulatory on hypertrophic contractility isolated When repetitively injected two different mouse models serum levels, aggravated hypertrophy. also novel procedure synthesis purification recombinant anti-hypertrophic FGF23-treated Thus, independent co-receptors opposite pathologic actions FGF23, reducing increasing FGF23-induced Hence, injections extremely high contribute their rates events mortality remains be studied. Translational StatementPatients have fibroblast (FGF23) dialysis, they receive infusions blood thinner. Our experimental show acts cofactor increases FGF23's affinity thereby aggravates heart. Hemodialysis does not reduce risk end-stage renal disease, future clinical should test frequent these removal from dialysis process might improve outcomes survival. serves major regulator phosphate metabolism.1Quarles L.D. 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