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F653, 2019. First published January 16, 2019; doi:10.1152/ajprenal. 00487.2018.--Zn2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn2+ in BP regulation, adult mice were fed a Zn2+-adequate (ZnA) or a Zn2+-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na+-Cl cotransporter (NCC) inhibitor. To reduce intracellular Zn2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N=,N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, a Zn2+ chelator)- or vehicle (DMSO)- containing medium. To replete intracellular Zn2+, TPEN-exposed cells were then cultured in Zn2+-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na+ excretion and NCC upregulation. These effects were reversed in Zn2+-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na+ uptake activity. Zn2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na+ handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension. [ABSTRACT FROM AUTHOR]

Zn 2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn 2+ in BP regulation, adult mice were fed a Zn 2+ -adequate (ZnA) or a Zn 2+ -deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na + -Cl - cotransporter (NCC) inhibitor. To reduce intracellular Zn 2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn 2+ chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn 2+ , TPEN-exposed cells were then cultured in Zn 2+ -supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na + excretion and NCC upregulation. These effects were reversed in Zn 2+ -replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn 2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na + uptake activity. Zn 2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn 2+ contributes to BP regulation via modulation of renal Na + transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn 2+ -regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na + handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn 2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.