Zinc deficiency induces hypertension by promoting renal Na⁺ reabsorption

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.