Nox2 is a mediator of ischemia reperfusion injury.

Abstract

Delayed graft function (DGF) results from ischemia-reperfusion injury (IRI) and the generation of reactive oxygen species. We hypothesized that NADPH oxidase 2 (Nox2) plays an important role in pathways leading to DGF. We tested this hypothesis in vitro, in an animal model of IRI using wild type and Nox2(-/-) mice, and in patients with DGF. Under hypoxic conditions, primary tubular epithelial cells from Nox2(-/-) mice had reduced expression of MMP2, vimentin, and HSP27. BUN and creatinine levels were significantly increased in both Nox2(-/-) and WT mice at 4 weeks and 6 months after IRI, suggesting the development of acute and chronic kidney injury. At 4 weeks, kidney fibrosis (α-SMA, picrosirius) and oxidative stress (dihydroethidine, HNE) were significantly reduced in Nox2(-/-) mice, confirming the oxidative and pro-fibrotic effects of Nox2. The molecular signature of IRI using genomic analyses demonstrated a significant decline in hypoxia reponse, oxidative stress, fibrosis, and inflammation in Nox2(-/-) mice. Immunohistochemical analyses of pre-implanatation kidney allograft biopsies from patients with subsequent DGF showed significantly greater Nox2 levels and vascular injury compared with patients without DGF. These studies demonstrate that Nox2 is a modulator of IRI and its absence is associated with reduced inflammation, OS, and fibrosis.

• Authors: A S Karim, S R Reese, N A Wilson, L M Jacobson, W Zhong, A Djamali
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 15 Issue 11 Pg. 2888-99 (Nov 2015) ISSN: 1600-6143 [Electronic] United States
• PMID: 26104383 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• Biomarkers
• Membrane Glycoproteins
• RNA, Small Interfering
• Reactive Oxygen Species
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases

Topics

• Analysis of Variance
• Animals
• Biomarkers (metabolism)
• Case-Control Studies
• Delayed Graft Function (metabolism, pathology)
• Disease Models, Animal
• Female
• Fibrosis (pathology)
• Humans
• Immunoblotting
• Immunohistochemistry
• Kidney Function Tests
• Kidney Transplantation (adverse effects)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (metabolism)
• Nephrectomy (adverse effects, methods)
• Oxidative Stress (physiology)
• RNA, Small Interfering (metabolism)
• Random Allocation
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (metabolism, pathology)
• Statistics, Nonparametric