Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity

Abstract

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. 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 H2O2.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. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH–dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2–mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.

NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

“…However, patients with microalbuminuria showed higher NOX1, but lower NOX2, levels compared to normotensive individuals (S1 Fig). The higher NOX1 levels in those patients is in agreement with previous preclinical data showing that NOX1 is not associated with elevation of blood pressure but with renal oxidative stress in a model of chronic hypertension [6] and renal pathology [31][32][33].…”

Inhibition of NOX4/ROS Suppresses Neuronal and Blood-Brain Barrier Injury by Attenuating Oxidative Stress After Intracerebral Hemorrhage

“…NOX4 is situated in the plasma membrane, where it delivers electrons through the plasma membrane to produce ROS (Nishimura et al, 2016). Although first discovered in the kidney, NOX4 is also present in the central nervous system, mainly expressed in neurons and the vascular endothelium (Takac et al, 2012;Muñoz et al, 2019). Previously, researchers focused on the manifestation of the NOX2 subtype in the pathological evolution of various neurological diseases (Haslund-Vinding et al, 2017).…”

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

“…•− derived from Nox1. In contrast, reduced endothelial Nox4 expression associated with reduced H 2 O 2 production and H 2 O 2 -mediated vasodilation may hamper the protective function of Nox4 on the kidneys, thus contributing to kidney damage [22]. A unique role is attributed to the Nox4 isoform.…”