Nox2 Is a Mediator of Ischemia Reperfusion Injury

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. Using in vitro, animal and translational studies, the investigators demonstrate that Nox2 is a modulator of ischemia‐reperfusion injury and associate its absence with reduced inflammation, oxidative stress, and fibrosis.