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Mech Ageing Dev. 2015 Dec;152:43-55. doi: 10.1016/j.mad.2015.10.001. Epub 2015 Oct 20.

Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation.

Author information

1
Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain; RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
2
University of Alabama at Birmingham, USA.
3
RedinREn from ISCIII, Madrid, Spain; Bone and Mineral Research Unit, Asturias Central University Hospital, 33006 Oviedo, Spain.
4
Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
5
RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain; Nephrology unit, Príncipe de Asturias University Hospital, 28871 Alcalá de Henares, Madrid, Spain.
6
Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain; RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain. Electronic address: mpiedad.ruiz@uah.es.

Abstract

Aging is conditioned by genetic and environmental factors. Hyperphosphatemia is related to some pathologies, affecting to vascular cells behavior. This work analyze whether high concentration of extracellular phosphate induces vascular smooth muscle cells senescence, exploring the intracellular mechanisms and highlighting the in vivo relevance of this phenomenon. Human aortic smooth muscle cells treated with β-Glycerophosphate (BGP, 10mM) suffered cellular senescence by increasing p53, p21 and p16 expression and the senescence associated β-galactosidase activity. In parallel, BGP induced ILK overexpression, dependent on the IGF-1 receptor activation, and oxidative stress. Down-regulating ILK expression prevented BGP-induced senescence and oxidative stress. Aortic rings from young rats treated with 10mM BGP for 48h, showed increased p53, p16 and ILK expression and SA-β-gal activity. Seven/eight nephrectomized rats feeding a hyperphosphatemic diet and fifteenth- month old mice showed hyperphosphatemia and aortic ILK, p53 and p16 expression. In conclusion, we demonstrated that high extracellular concentration of phosphate induced senescence in cultured smooth muscle through the activation of IGF-1 receptor and ILK overexpression and provided solid evidences for the in vivo relevance of these results since aged animals showed high levels of serum phosphate linked to increased expression of ILK and senescence genes.

KEYWORDS:

hyperphosphatemia; integrin linked kinase; senescence; vascular smooth muscle cells

PMID:
26467393
DOI:
10.1016/j.mad.2015.10.001
[Indexed for MEDLINE]

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