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Nox2 and Cyclosporine-Induced Renal Hypoxia
#MMPMID26950727
Djamali A
; Wilson NA
; Sadowski EA
; Zha W
; Niles D
; Hafez O
; Dorn JR
; Mehner TR
; Grimm PC
; Hoffmann FM
; Zhong W
; Fain SB
; Reese SR
Transplantation
2016[Jun]; 100
(6
): 1198-210
PMID26950727
show ga
BACKGROUND: We hypothesized that nicotinamide adenosine diphosphate oxidase 2
(Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia.
METHODS: We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and
Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity.
We used noninvasive molecular imaging (blood oxygen level-dependent magnetic
resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and
molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and
the molecular phenotype of CsA nephrotoxicity. RESULTS: We observed that chemical
and genetic inhibition of Nox2 in rats and mice resulted in the prevention of
CsA-induced hypoxia independent of regional perfusion (blood oxygen
level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic
resonance imaging, pimonidazole, HIF-1?). Nicotinamide adenosine diphosphate
oxidase 2 knockout was also associated with decreased oxidative stress (Nox2,
HIF-1?, hydrogen peroxide, hydroxynonenal), and fibrogenesis (?-smooth muscle
actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic
CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes
in 40 genes involved in injury repair, metabolism, and oxidative stress in
Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver
transplant recipients with chronic CsA nephrotoxicity showed significantly
greater Nox2, ?-smooth muscle actin and picrosirius levels compared with
controls. CONCLUSIONS: These studies suggest that Nox2 is a modulator of
CsA-induced hypoxia upstream of HIF-1? and define the molecular characteristics
that could be used for the diagnosis and monitoring of chronic calcineurin
inhibitor nephrotoxicity.
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