title: Glucose Oxidase Induces Cellular Senescence in Immortal Renal Cells through ILK by Downregulating Klotho Gene Expression.
abstract: Cellular senescence can be prematurely induced by oxidative stress involved in aging. In this work, we were searching for novel intermediaries in oxidative stress-induced senescence, focusing our interest on integrin-linked kinase (ILK), a scaffold protein at cell-extracellular matrix (ECM) adhesion sites, and on the Klotho gene. Cultured renal cells were treated with glucose oxidase (GOx) for long time periods. GOx induced senescence, increasing senescence associated β-galactosidase activity and the expression of p16. In parallel, GOx increased ILK protein expression and activity. Ectopic overexpression of ILK in cells increased p16 expression, even in the absence of GOx, whereas downregulation of ILK inhibited the increase in p16 due to oxidative stress. Additionally, GOx reduced Klotho gene expression and cells overexpressing Klotho protein did not undergo senescence after GOx addition. We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex. In conclusion, oxidative stress induces cellular senescence in kidney cells by increasing ILK protein expression and activity, which in turn reduces Klotho expression. We hereby present ILK as a novel downregulator of Klotho gene expression.
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Troyano-Suárez
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: María
authors.initials: M
authors.lastname: del Nogal-Avila
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Mora
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sosa
authors.affiliation: Unidad de Investigación, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28871 Madrid, Spain ; Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: López-Ongil
authors.affiliation: Unidad de Investigación, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28871 Madrid, Spain ; Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain ; Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Olmos
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain ; Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
authors.forename: María Piedad
authors.initials: MP
authors.lastname: Ruíz-Torres
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005949:Glucose Oxidase / Q000494:pharmacology*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D000090265:Klotho Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D005949:Glucose Oxidase; D005966:Glucuronidase; D000090265:Klotho Proteins; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D000099200:Scaffold Protein ILK