The protective effects of
nicotinamide adenine dinucleotide phosphate (
NADPH) oxidase (NOX) 1 inhibition against kidney
ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin-Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress.
ML171, a selective NOX1 inhibitor, and
siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and
mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of
reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by
ML171. H2O2 evoked the changes in oxidative stress
enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by
ML171. Treatment with
ML171 and transfection with
siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells.
ML171 decreased
caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways,
ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.