Zinc Deficiency Drives Renal NFkB Activation

Abstract

Background Zn2+ 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. Hypothesis As such, we hypothesized that ZnD drives renal NFκB activation. Experimental Design To 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,Nʹ,Nʹ-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) or vehicle ± Zn2+ supplementation. Results In 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. Conclusion These results indicate that 1) NFκB is a Zn2+-regulated nuclear transcription factor, and 2) ZnD drives renal NFkB activation. Significance NFκB represents a potential mediator that drives ZnD-induced NCC upregulation and consequently renal Na+ reabsorption and hypertension.