The calcimimetic etelcalcetide restores cardiac function in chronic hyperphosphatemia via calcium sensing receptor-cAMP activation: basic research
Introduction - The cardioprotective properties of the calcimimetic etelcalcetide (Etel) in the setting of hyperphosphatemia are largely unknown. - Methods - To study this, male C57BL/6N mice were fed a high-phosphate diet (HPD, 2.0%) for six months without/with Etel or vehicle administration during...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 2026
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| In: |
Kidney international
Year: 2026, Volume: 110, Issue: 2, Pages: 400-412 |
| ISSN: | 1523-1755 |
| DOI: | 10.1016/j.kint.2026.03.018 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.kint.2026.03.018 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S008525382600308X 
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| Author Notes: | Andrea Grund, Isabel Manegold, Gloria Sophie Richter, Beatrice Richter, Martina Thiele, Louise H. Baer, Kathrin Kowalski, Theresia Kraft, Thomas Thum, Felix A. Trogisch, Jörg Heineke, Dieter Haffner and Maren Leifheit-Nestler |
| Summary: | Introduction - The cardioprotective properties of the calcimimetic etelcalcetide (Etel) in the setting of hyperphosphatemia are largely unknown. - Methods - To study this, male C57BL/6N mice were fed a high-phosphate diet (HPD, 2.0%) for six months without/with Etel or vehicle administration during months four to six, or they were fed a normal phosphate diet (NPD, 0.8%). Cardiac function was investigated by echocardiography and Millar catheter. Heart tissue was taken for RNAseq, and cardiomyocyte morphology and cardiac fibrosis were evaluated histologically. Isolated adult mouse cardiomyocytes (AMCMs) from NPD and HPD groups and from untreated mice after acute exposure to phosphate, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) with/without Etel were used to assess cardiomyocyte contractility and calcium transients. The calcium sensing receptor (CaSR)/cAMP/phospholamban (PLB)/Serca2a signaling pathway was investigated by Western blot and activity assays. To test if the cardiac effects of Etel and phosphate are directly mediated by the CaSR, AMCMs pretreated with the CaSR antagonist NPS-2143 or an adenoviral expression of a phosphate binding-deficient CaSR mutant (CaSR-R62A) were used. - Results - Six-month HPD resulted in hyperphosphatemia, increased PTH and FGF23 concentrations, impaired systolic cardiac function and cardiomyocyte contractility, and cardiac hypertrophy and fibrosis. Etel prevented systolic dysfunction and fibrosis and normalized PTH and FGF23 levels despite persistent hyperphosphatemia. RNAseq analysis revealed HPD induced remodeling programs, with suppression of calcium and contractility signaling, which was ameliorated by Etel. Isolated cardiomyocytes from HPD mice showed impaired contractility and calcium transients, both of which were rescued by Etel. Ex vivo phosphate stimulation of AMCMs reduced contractility, calcium transients, cAMP formation, PLB phosphorylation, and Serca2a activity compared with vehicle; these effects were rescued by Etel co-stimulation. Transduction with CaSR-R62A abolished phosphate-induced effects in AMCMs, whereas pretreatment with NPS-2143 prevented Etel rescue. - Conclusions - Etelcalcetide restores hyperphosphatemia-induced cardiac dysfunction via activation of the CaSR. |
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| Item Description: | Online verfügbar: 25. April 2026, Artikelversion: 20. Juli 2026 Gesehen am 20.08.2026 |
| Physical Description: | Online Resource |
| ISSN: | 1523-1755 |
| DOI: | 10.1016/j.kint.2026.03.018 |