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2015 ; 15
(11
): 2888-99
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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
PMID26104383
show 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.