Hydrogen peroxide derived from NADPH oxidase 4- and 2 contributes to the endothelium-dependent vasodilatation of intrarenal arteries

Abstract

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (H2O2) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator H2O2 in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O2.-) and H2O2 production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O2.- and H2O2 production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated H2O2 production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of H2O2 generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature.

Liraglutide Improves the Kidney Function in a Murine Model of Chronic Kidney Disease

“…Moreover, liraglutide upregulated NOX4 (NADPH oxidase 4), which has been demonstrated to provide beneficial effects on vasodilator function in mice and rat renal arterioles by production of hydrogen peroxide [34, 35]. Surprisingly, the expression of NOS3 which synthesizes nitric oxide (NO) was downregulated by liraglutide in the NTN model.…”

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

“…Within the vasculature, ROS contribute to basal endothelial cell proliferation/migration [ 39 , 40 ], as well as smooth muscle cell differentiation [ 41 ]. ROS can also participate in vasomotor responses such as autoregulation [ 42 ], endothelium-dependent vasodilation [ 43 , 44 ], flow-mediated vasodilation [ 45 ], hypoxic pulmonary vasoconstriction (HPV) [ 46 , 47 ] and hyperoxia-induced vasoconstriction [ 48 , 49 , 50 ]. At physiological concentrations, H 2 O 2 elicits vasodilation in the pulmonary circulation [ 51 , 52 , 53 , 54 ] and diminishes HPV in CH animals [ 55 ].…”

NADPH oxidase inhibition rescues keratinocytes from elevated oxidative stress in a 2D atopic dermatitis and psoriasis model

“…The novel inhibitors ML171 and GKT136901 selectively inhibit NOX1 and NOX1/NOX4, respectively. [46][47][48][49][50] Clinical trials with 170 patients have demonstrated that the novel inhibitors are well-tolerated and non-toxic, and thus provide a good alternative for DPI. [50] In this study, we controlled for the possible unspecific effects of DPI by additionally analysing intracellular ROS levels after inhibition of NOX1 and NOX1/4 by the selective inhibitors.…”