Abstract
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.
Highlights
Kidney ischemia/reperfusion injury (IRI), which is the interruption and restoration of blood flow, is a basic pathophysiology of acute kidney injury associated with high mortality and morbidity
Previous studies have reported that NOX1 upregulation was involved in cisplatin-induced kidney injury [13] and NOX1 inhibitor has a protective effect on lung IRI by suppressing inflammatory and autophagy activation [14]
blood urea nitrogen (BUN) and Cr levels were significantly increased by IRI compared to the control groups
Summary
Kidney ischemia/reperfusion injury (IRI), which is the interruption and restoration of blood flow, is a basic pathophysiology of acute kidney injury associated with high mortality and morbidity. NOX1-dependent ROS production contributes to cell signaling, cell growth, angiogenesis, motility, and blood pressure regulation [10,11,12]. Previous studies have reported that NOX1 upregulation was involved in cisplatin-induced kidney injury [13] and NOX1 inhibitor has a protective effect on lung IRI by suppressing inflammatory and autophagy activation [14]. Several antioxidants and anti-inflammatory agents [15,16,17,18,19] have effects on ROS production and inflammatory reactions, and NOX4 inhibitor [20] has been used in experimental studies to prevent or decrease IRI-induced kidney damage, the protective effect of NOX1 inhibition against kidney IRI is not totally understood
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