Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin‐1 production
| Autor: | Manuel Naves-Diaz, Leocadio Rodríguez-Mañas, Diana Medrano, Diego Rodríguez-Puyol, Susana López-Ongil, Patricia Martínez-Miguel, María Piedad Ruiz-Torres, Patricia Sosa, Gemma Olmos, Elena Alcalde-Estévez |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Senescence Aging medicine.medical_specialty senescence endothelin‐1 Cell 030204 cardiovascular system & hematology Biology Mice 03 medical and health sciences Hyperphosphatemia 0302 clinical medicine Internal medicine medicine Extracellular Animals Humans Rats Wistar Transcription factor Cellular Senescence reactive oxygen species chemistry.chemical_classification Reactive oxygen species Endothelin-1 Endothelial Cells Original Articles Cell Biology AP-1 medicine.disease AP‐1 Endothelin 1 Rats Mice Inbred C57BL AP-1 transcription factor 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Original Article |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | Summary 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-s-GAL) activity. ET-1 itself was able to induce endothelial senescence, increasing p16 expression and SA-s-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. |
| Databáze: | OpenAIRE |
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