Zinc Deficiency Drives Renal NFkB Activation

Background: Zinc deficiency (ZnD) is comorbid with life-threatening diseases such as diabetes and kidney disease. In these populations, the prevalence of hypertension is elevated. In our published studies, we demonstrated that ZnD alone was sufficient in promoting hypertension in hypertensive-resistant mice. Specifically, our findings revealed that hypertension was a consequence of renal sodium retention. However, the underlying molecular mechanisms driving these effects were undefined. Hypothesis: Since the transcription factor nuclear factor-κB (NFκB) is implicated in the pathogenesis of hypertension, we tested the hypothesis that ZnD drives renal NFκB activation. Experimental Design: To examine the impact of ZnD on renal NFκB, adult male C57Bl/6 mice were fed a zinc deficient or zinc adequate diet for 10 weeks. Both NFκB expression and nuclear translocation were examined by immunofluorescence and Western blot. To directly investigate the role of zinc in NFκB regulation, mouse tubule epithelial cells were exposed to medium containing a zinc chelator (N, N, N', N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine, TPEN) or vehicle for 24 hours. To examine whether ZnD-induced effects on NFκB were reversible, the medium of TPEN-exposed cells were supplemented with zinc. Results: While NFκB expression was undetectable in zinc adequate mice, its expression and nuclear localization were enhanced in zinc deficient mice, as assessed by both immunofluorescence and Western blot. Interestingly, immunofluorescence revealed increased NFκB expression and nuclear localization exclusively in selected tubules. Consistently, our in vitro model demonstrated that TPEN-induced ZnD also promoted NFκB expression and nuclear translocation. Notably, zinc repletion reversed TPEN-induced NFκB upregulation. Conclusions: Collectively, both in vivo and in vitro findings reveal that 1) renal NFκB is a zinc-regulated nuclear transcription factor and 2) ZnD drives NFκB upregulation in selected tubular epithelial cells. Significance: Importantly, this study identifies NFκB as a potential mediator of ZnD-induced renal sodium retention and subsequently hypertension. Funding Source: AHA-16SDG27080009 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.