ET ‐1 increases reactive oxygen species following hypoxia and high‐salt diet in the mouse glomerulus

Aim This study was designed to determine whether ET ‐1 derived from endothelial cells contributes to oxidative stress in the glomerulus of mice subjected to a high‐salt diet and/or hypoxia. Methods C57 BL 6/J control mice or vascular endothelial cell ET ‐1 knockout ( VEET KO ) mice were subjected to 3‐h exposure to hypoxia (8% O 2 ) and/or 2 weeks of high‐salt diet (4% NaCl) prior to metabolic cage assessment of renal function and isolation of glomeruli for the determination of reactive oxygen species ( ROS ). Results In control mice, hypoxia significantly increased urinary protein excretion during the initial 24 h, but only in animals on a high‐salt diet. Hypoxia increased glomerular ET‐1 mRNA expression in control, but not in vascular endothelial cell ET‐1 knockout (VEET KO) mice. Under normoxic conditions, mice on a high‐salt diet had approx. 150% higher glomerular ET‐1 mRNA expression compared with a normal‐salt diet ( P  < 0.05). High‐salt diet administration significantly increased glomerular ROS production in flox control, but not in glomeruli isolated from VEET KO mice. In C57BL6/J mice, the ET A receptor‐selective antagonist, ABT‐627, significantly attenuated the increase in glomerular ROS production produced by high‐salt diet. In addition, chronic infusion of C57BL6/J mice with a subpressor dose of ET‐1 (osmotic pumps) significantly increased the levels of glomerular ROS that were prevented by ET A antagonist treatment. Conclusion These data suggest that both hypoxia and a high‐salt diet increase glomerular ROS production via endothelial‐derived ET ‐1‐ ET A receptor activation and provide a potential mechanism for ET ‐1‐induced nephropathy.