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Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 416738, 13 pages
http://dx.doi.org/10.1155/2015/416738
Research Article

Glucose Oxidase Induces Cellular Senescence in Immortal Renal Cells through ILK by Downregulating Klotho Gene Expression

1Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain
2University of Alabama at Birmingham, Birmingham, AL, USA
3Unidad de Investigación, Fundación para la Investigación Biomédica del Hospital Universitario Príncipe de Asturias, Alcalá de Henares, 28871 Madrid, Spain
4Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain

Received 8 April 2015; Accepted 17 May 2015

Academic Editor: Claudio Cabello-Verrugio

Copyright © 2015 Nuria Troyano-Suárez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.