NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H<sub>2</sub>O<sub>2</sub>.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity.
Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress.
ISMN/ISDN treatment caused activation of the NOX-2/ET receptor signaling axis leading to increased vascular oxidative stress and inflammation as well as endothelial dysfunction.
This was paralleled by decreased hepatic and aortic reactive oxygen species (ROS) production and NOX-2 mRNA expression, a normalization of endothelial dysfunction, cardiac NADPH oxidase activity, mitochondrial ROS formation, and whole blood oxidative burst in the MCD model.
Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia.
The effect of metabolic disorder on Nox2 activation and endothelial dysfunction was further confirmed using high-fat diet-induced obesity and insulin resistance in middle-aged WT mice treated with apocynin (a Nox2 inhibitor).
Dh404 significantly attenuated endothelial dysfunction in diabetic Akita mice characterized by reduced contraction in response to phenylephrine and the downregulation of inflammatory genes (VCAM-1, ICAM-1, p65, IL-1β) and pro-oxidant genes (Nox1 and Nox2).
These results provide the first evidence that plasma from PE generates superoxide via a LOX1-NOX2-mediated pathway and downregulates endothelial KCa3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia.
Moreover, the HG-induced effect including ceramide production, LRs clustering, gp91(phox) colocalization to LRs clusters, O₂·⁻ formation and endothelial dysfunction could be blocked significantly by the inhibition of lysosome-membrane fusion.