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ET ‐1 increases reactive oxygen species following hypoxia and high‐salt diet in the mouse glomerulus
Author(s) -
Heimlich J. B.,
Speed J. S.,
Bloom C. J.,
O'Connor P. M.,
Pollock J. S.,
Pollock D. M.
Publication year - 2015
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12397
Subject(s) - medicine , endocrinology , reactive oxygen species , hypoxia (environmental) , oxidative stress , biology , receptor , chemistry , oxygen , biochemistry , organic chemistry
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.