Zinc deficiency induces hypertension by promoting renal Na+ reabsorption

Clintoria R. Williams*, Monisha Mistry, Aswathy M. Cheriyan, Jasmine M. Williams, Meagan K. Naraine, Carla LaShannon Ellis, Rickta Mallick, Abinash C. Mistry, Jennifer L. Gooch, Benjamin Ko, Hui Cai, Robert S. Hoover

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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-pyridylmet-hyl)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.

Original languageEnglish (US)
Pages (from-to)F646-F653
JournalAmerican Journal of Physiology - Renal Physiology
Volume316
Issue number4
DOIs
StatePublished - Apr 2019

Keywords

  • Blood pressure
  • Hypertension
  • Kidney
  • Sodium-chloride cotransporter
  • Zinc deficiency

ASJC Scopus subject areas

  • Physiology
  • Urology

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