title: Hyperphosphatemia induces cellular senescence in human aorta smooth muscle cells through integrin linked kinase (ILK) up-regulation.
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.
authors.affiliation: Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain; RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Troyano
authors.affiliation: University of Alabama at Birmingham, USA.
authors.forename: María Del
authors.initials: MD
authors.lastname: Nogal
authors.affiliation: Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain; RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Mora
authors.affiliation: RedinREn from ISCIII, Madrid, Spain; Bone and Mineral Research Unit, Asturias Central University Hospital, 33006 Oviedo, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Diaz-Naves
authors.affiliation: RedinREn from ISCIII, Madrid, Spain; Bone and Mineral Research Unit, Asturias Central University Hospital, 33006 Oviedo, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lopez-Carrillo
authors.affiliation: Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sosa
authors.affiliation: RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain; Nephrology unit, Príncipe de Asturias University Hospital, 28871 Alcalá de Henares, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.affiliation: Department of System Biology, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain; RedinREn from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Olmos
authors.affiliation: 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.
authors.forename: María P
authors.initials: MP
authors.lastname: Ruiz-Torres
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D054559:Hyperphosphatemia / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK
keywords: hyperphosphatemia; integrin linked kinase; senescence; vascular smooth muscle cells