Zinc Deficiency‐Induced Renal NFkB Activation drives Sodium Chloride Co‐transporter Upregulation.

Abstract

BackgroundZn2+ deficiency (ZnD) is a worldwide problem. In the United States, 14% of Americans are Zn2+ deficient, which represents 1 out of 7 people. In ZnD populations, the prevalence of hypertension is higher. In our recent studies, we demonstrated that ZnD induces hypertension by promoting renal Na+ reabsorption by the sodium chloride co‐transporter (NCC). However, the exact molecular mechanisms involved in NCC upregulation were undefined. Nuclear factor‐κB (NFκB) is a transcription factor found to play a role in ZnD‐mediated detrimental effects throughout the body.HypothesisAs such, we hypothesized that ZnD drives renal NFκB activation.Experimental DesignTo examine the effects of ZnD on renal NFκB activation, adult, male C57Bl/6 mice were fed a ZnA‐ or ZnD‐diet for 6 weeks. NFκB expression and nuclear translocation were examined by immunohistochemistry. To confirm the role of Zn2+ in NFκB regulation, mouse distal convoluted tubular (mDCT) cells were treated with the Zn2+ chelator ‐ N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethane‐1,2‐diamine (TPEN) or vehicle ± Zn2+ supplementation.ResultsIn ZnD mice, NFκB protein expression and nuclear localization were increased compared to ZnA mice. Consistently, in mDCT cells, TPEN‐induced ZnD stimulated NFκB expression and nuclear translocation. However, Zn2+ supplementation reversed TPEN‐induced NFκB upregulation.ConclusionThese results indicate that 1) NFκB is a Zn2+‐regulated nuclear transcription factor, and 2) ZnD drives renal NFkB activation.SignificanceNFκB represents a potential mediator that drives ZnD‐induced NCC upregulation and consequently renal Na+ reabsorption and hypertension.Support or Funding InformationAmerican Heart Association ‐ Scientist Development Grant #16SDG27080009 National Institutes of Health ‐ R21 Exploratory/Development Grant #R21DK119879