Hyperphosphatemia induces senescence in human endotelial cells by increasing endothelin-1 production
Authors
Olmos Centenera, Gemma; Martínez Miguel, Patricia; Alcalde Estévez, Elena; Medrano Andrés, Diana; Sosa Callejas, Patricia; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/60286DOI: 10.1111/acel.12664
ISSN: 1474-9718
Date
2017-08-01Affiliation
Universidad de Alcalá. Departamento de Medicina y Especialidades Médicas; Universidad de Alcalá. Departamento de Biología de Sistemas. Unidad Docente de FisiologíaFunders
Instituto de Salud Carlos III
Fundación de Investigación Biomédica Príncipe de Asturias
Bibliographic citation
Aging Cell, 2017, v. 16, n. , p. 1300-1312
Keywords
AP‐1
Endothelin‐1
Endothelial cells
Hyperphosphatemia
Reactive oxygen species
Senescence
Description / Notes
15 p.
Project
info:eu-repo/grantAgreement/ISCIII/FIS/PI13%02270/ES//
info:eu-repo/grantAgreement/ISCIII/FIS/PI13%00336/ES//
info:eu-repo/grantAgreement/ISCIII/FIS/ PI13%00014/ES//
info:eu-repo/grantAgreement/ISCIII/FIS/ PI16%02082/ES//
info:eu-repo/grantAgreement/ISCIII/FIS/ PI16/01619/ES//
info:eu-repo/grantAgreement/ISCIII/REDinREN/ RETIC REDinREN RD12%0021%0006/ES//
info:eu-repo/grantAgreement/ISCIII/REDinREN/ RETIC REDinREN RD12%0021%1023/ES//
info:eu-repo/grantAgreement/ISCIII/REDinREN/ RETIC REDinREN RD016%009/ES//
info:eu-repo/grantAgreement/FIBHUPA//FIB-PI13-01/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/acceptedVersion
Rights
©2017 The Author(s)
Attribution 4.0 International (CC BY 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
Hyperphosphatemia is related to some pathologies, affecting vascular cell behavior. This work analyzes whether high concentration of extracellular phosphate induces endothelial senescence through up‐regulation of endothelin‐1 (ET‐1), exploring the mechanisms involved. The phosphate donor β‐glycerophosphate (BGP) in human endothelial cells increased ET‐1 production, endothelin‐converting enzyme‐1 (ECE‐1) protein, and mRNA expression, which depend on the AP‐1 activation through ROS production. In parallel, BGP also induced endothelial senescence by increasing p16 expression and the senescence‐associated β‐galactosidase (SA‐ß‐GAL) activity. ET‐1 itself was able to induce endothelial senescence, increasing p16 expression and SA‐ß‐GAL activity. In addition, senescence induced by BGP was blocked when different ET‐1 system antagonists were used. BGP increased ROS production at short times, and the presence of antioxidants prevented the effect of BGP on AP1 activation, ECE‐1 expression, and endothelial senescence. These findings were confirmed in vivo with two animal models in which phosphate serum levels were increased: seven/eight nephrectomized rats as chronic kidney disease models fed on a high phosphate diet and aged mice. Both models showed hyperphosphatemia, higher levels of ET‐1, and up‐regulation in aortic ECE‐1, suggesting a direct relationship between hyperphosphatemia and ET‐1. Present results point to a new and relevant role of hyperphosphatemia on the regulation of ET‐1 system and senescence induction at endothelial level, both in endothelial cells and aorta from two animal models. The mechanism involved showed a higher ROS production, which probably activates AP‐1 transcription factor and, as a result, ECE‐1 expression, increasing ET‐1 synthesis, which in consequence induces endothelial senescence.
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