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In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn<jats:sup>2+<\/jats:sup> in BP regulation, adult mice were fed a Zn<jats:sup>2+<\/jats:sup>-adequate (ZnA) or a Zn<jats:sup>2+<\/jats:sup>-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na<jats:sup>+<\/jats:sup>-Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NCC) inhibitor. To reduce intracellular Zn<jats:sup>2+<\/jats:sup> in vitro, mouse distal convoluted tubule cells were cultured in N,N,N\u2032,N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn<jats:sup>2+<\/jats:sup> chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn<jats:sup>2+<\/jats:sup>, TPEN-exposed cells were then cultured in Zn<jats:sup>2+<\/jats:sup>-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na<jats:sup>+<\/jats:sup> excretion and NCC upregulation. These effects were reversed in Zn<jats:sup>2+<\/jats:sup>-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn<jats:sup>2+<\/jats:sup> depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na<jats:sup>+<\/jats:sup> uptake activity. Zn<jats:sup>2+<\/jats:sup> repletion reversed TPEN effects on NCC. These data indicate that 1) Zn<jats:sup>2+<\/jats:sup> contributes to BP regulation via modulation of renal Na<jats:sup>+<\/jats:sup> transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn<jats:sup>2+<\/jats:sup>-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na<jats:sup>+<\/jats:sup> handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn<jats:sup>2+<\/jats:sup> regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension. <\/jats:p>","DOI":"10.1152\/ajprenal.00487.2018","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T13:16:37Z","timestamp":1547644597000},"page":"F646-F653","source":"Crossref","is-referenced-by-count":55,"title":["Zinc deficiency induces hypertension by promoting renal Na<sup>+<\/sup> reabsorption"],"prefix":"10.1152","volume":"316","author":[{"given":"Clintoria R.","family":"Williams","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, and Department of Physiology, Emory University, Atlanta, Georgia"},{"name":"Research Service, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia"},{"name":"Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine, and College of Science and Mathematics, Wright State University, Dayton, 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