NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage.
Am J Physiol Cell Physiol
; 312(1): C47-C55, 2017 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-27806940
ABSTRACT
Zn2+ deficiency (ZnD) is comorbid with chronic kidney disease and worsens kidney complications. Oxidative stress is implicated in the detrimental effects of ZnD. However, the sources of oxidative stress continue to be identified. Since NADPH oxidases (Nox) are the primary enzymes that contribute to renal reactive oxygen species generation, this study's objective was to determine the role of these enzymes in ZnD-induced oxidative stress. We hypothesized that ZnD promotes NADPH oxidase upregulation, resulting in oxidative stress and kidney damage. To test this hypothesis, wild-type mice were pair-fed a ZnD or Zn2+-adequate diet. To further investigate the effects of Zn2+ bioavailability on NADPH oxidase regulation, mouse tubular epithelial cells were exposed to the Zn2+ chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn2+ supplementation. We found that ZnD diet-fed mice develop microalbuminuria, electrolyte imbalance, and whole kidney hypertrophy. These markers of kidney damage are accompanied by elevated Nox2 expression and H2O2 levels. In mouse tubular epithelial cells, TPEN-induced ZnD stimulates H2O2 generation. In this in vitro model of ZnD, enhanced H2O2 generation is prevented by NADPH oxidase inhibition with diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation, which are reversed when intracellular Zn2+ levels are restored following Zn2+ supplementation. Finally, Nox2 knockdown by siRNA prevents TPEN-induced H2O2 generation and cellular hypertrophy in vitro. Together, these findings reveal that Nox2 is a Zn2+-regulated enzyme that mediates ZnD-induced oxidative stress and kidney hypertrophy. Understanding the specific mechanisms by which ZnD contributes to kidney damage may have an important impact on the treatment of chronic kidney disease.
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Base de dados:
MEDLINE
Assunto principal:
Zinco
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Estresse Oxidativo
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NADPH Oxidases
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Insuficiência Renal Crônica
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Rim
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article