Zinc deficiency induces hypertension by promoting renal Na reabsorption.

Zn 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 in BP regulation, adult mice were fed a Zn-adequate (ZnA) or a Zn-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 in vitro, mouse distal convoluted tubule cells were cultured in N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn, TPEN-exposed cells were then cultured in Zn-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-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na uptake activity. Zn repletion reversed TPEN effects on NCC. These data indicate that 1) Zn contributes to BP regulation via modulation of renal Na transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn-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 regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.