Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction.
Τίτλος | Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Eleftheriadis, T., Pissas G., Antoniadi G., Liakopoulos V., & Stefanidis I. |
Journal | Int Urol Nephrol |
Volume | 50 |
Issue | 1 |
Pagination | 179-186 |
Date Published | 2018 Jan |
ISSN | 1573-2584 |
Λέξεις κλειδιά | Allopurinol, Cell Survival, Cells, Cultured, Endothelial Cells, Free Radical Scavengers, Glucose, Humans, Intercellular Adhesion Molecule-1, Kidney Glomerulus, Nitric Oxide Synthase, Primary Cell Culture, Reactive Oxygen Species, Tumor Suppressor Protein p53 |
Abstract | PURPOSE: Mitochondrial reactive oxygen species (ROS) overproduction in capillary endothelial cells is a prerequisite for the development of diabetic nephropathy. Inhibition of xanthine oxidase, another ROS generator, ameliorates experimental diabetic nephropathy. To test the hypothesis that the initial high glucose-induced ROS production by the mitochondria activates xanthine oxidase, which afterward remains as the major source of ROS, we cultured primary human glomerular endothelial cells (GEnC) under normal or high-glucose conditions, with or without the xanthine oxidase inhibitor allopurinol.METHODS: ROS generation and nitric oxide synthase (NOS) activity were assessed by chemiluminescence or colorimetrically. Levels of intercellular adhesion molecule 1 (ICAM-1), p53 and phosphorylated p53 (p-p53) were assessed by western blotting.RESULTS: Allopurinol prevented high glucose-induced ROS generation indicating that xanthine oxidase is the major source of ROS. Allopurinol protected GEnC from endothelial dysfunction since it prevented the high glucose-induced decrease in NOS activity and increase in ICAM-1 expression. Allopurinol reduced p53 and p-p53 levels induced by high glucose suggesting an axis of xanthine oxidase-derived ROS, DNA damage, p53 stabilization and endothelial dysfunction that may contribute to the pathogenesis of diabetic nephropathy.CONCLUSIONS: Allopurinol protects GEnC from high glucose-induced ROS generation, p53 overexpression and endothelial dysfunction. These data provide a pathogenetic mechanism that supports the results of experimental and clinical studies about the beneficial effect of xanthine oxidase inhibitors on the development of diabetic nephropathy. |
DOI | 10.1007/s11255-017-1733-5 |
Alternate Journal | Int Urol Nephrol |
PubMed ID | 29094329 |