Hungarian Research FundOrszagos Tudomanyos Kutatasi Alapprogramok(OTKA SNN-114619)
(ANN-110810) Támogató: Hungarian National Research, Development and Innovation Office
(K 145998)
(KKP-129954)
Upregulation of free radical-generating NADPH oxidases (NOX), xanthine oxidoreductase
(XOR), and neutrophil infiltration-induced, NOX2-mediated respiratory burst contribute
to renal ischemia–reperfusion injury (IRI), but their roles may depend on the severity
of IRI. We investigated the role of NOX, XOR, and neutrophils in developing IRI of
various severities. C57BL/6 and Mcl-1ΔMyelo neutrophil-deficient mice were used. Oxidases
were silenced by RNA interference (RNAi) or pharmacologically inhibited. Kidney function,
morphology, immunohistochemistry and mRNA expression were assessed. After reperfusion,
the expression of NOX enzymes and XOR increased until 6 h and from 15 h, respectively,
while neutrophil infiltration was prominent from 3 h. NOX4 and XOR silencing or pharmacological
XOR inhibition did not protect the kidney from IRI. Attenuation of NOX enzyme-induced
oxidative stress by apocynin and neutrophil deficiency improved kidney function and
ameliorated morphological damage after mild but not moderate/severe IRI. The IR-induced
postischemic renal functional impairment (BUN, Lcn-2), tubular necrosis score, inflammation
(TNF-α, F4/80), and decreases in the antioxidant enzyme (GPx3) mRNA expression were
attenuated by both apocynin and neutrophil deficiency. Inhibition of NOX enzyme-induced
oxidative stress or the lack of infiltration by NOX2-expressing neutrophils can attenuate
reperfusion injury after mild but not moderate/severe renal IR.
