Nox2 is a Mediator of Ischemia Reperfusion Injury #MMPMID26104383
Karim AS; Reese SR; Wilson NA; Jacobson LM; Zhong W; Djamali A
Am J Transplant 2015[Nov]; 15 (11): 2888-99 PMID26104383show ga
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 (?-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.
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Am+J+Transplant 2015 ; 15 (11): 2888-99
