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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 Zn<jats:sup>2+<\/jats:sup>-adequate diet. To further investigate the effects of Zn<jats:sup>2+<\/jats:sup> bioavailability on NADPH oxidase regulation, mouse tubular epithelial cells were exposed to the Zn<jats:sup>2+<\/jats:sup> chelator N,N,N\u2032,N\u2032-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn<jats:sup>2+<\/jats:sup> 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 H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> levels. In mouse tubular epithelial cells, TPEN-induced ZnD stimulates H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation. In this in vitro model of ZnD, enhanced H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation is prevented by NADPH oxidase inhibition with diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation, which are reversed when intracellular Zn<jats:sup>2+<\/jats:sup> levels are restored following Zn<jats:sup>2+<\/jats:sup> supplementation. Finally, Nox2 knockdown by siRNA prevents TPEN-induced H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation and cellular hypertrophy in vitro. Together, these findings reveal that Nox2 is a Zn<jats:sup>2+<\/jats:sup>-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. <\/jats:p>","DOI":"10.1152\/ajpcell.00208.2016","type":"journal-article","created":{"date-parts":[[2016,11,3]],"date-time":"2016-11-03T02:14:52Z","timestamp":1478139292000},"page":"C47-C55","source":"Crossref","is-referenced-by-count":64,"title":["NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage"],"prefix":"10.1152","volume":"312","author":[{"given":"Mirandy S.","family":"Li","sequence":"first","affiliation":[{"name":"School of Medicine, Emory University, Atlanta, Georgia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry E.","family":"Adesina","sequence":"additional","affiliation":[{"name":"School of Medicine, Emory University, Atlanta, Georgia;"},{"name":"Atlanta Veterans Affairs Medical Center, Atlanta, 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