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Zinc Deficiency‐Induced Renal NFkB Activation drives Sodium Chloride Co‐transporter Upregulation.
Author(s) -
Wenegieme Tara-Yesomi,
Waite Aston,
Naraine Meagan,
Murta Cindellynn,
Schindele Dylan,
Sonner Martha,
Williams Clintoria
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00720
Subject(s) - downregulation and upregulation , chemistry , medicine , nf κb , endocrinology , homeostasis , transcription factor , transporter , kidney , immunohistochemistry , sodium , biology , signal transduction , biochemistry , gene , organic chemistry
Background Zn 2+ deficiency (ZnD) is a worldwide problem. In the United States, 14% of Americans are Zn 2+ 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 Zn 2+ in NFκB regulation, mouse distal convoluted tubular (mDCT) cells were treated with the Zn 2+ chelator ‐ N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethane‐1,2‐diamine (TPEN) or vehicle ± Zn 2+ 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, Zn 2+ supplementation reversed TPEN‐induced NFκB upregulation. Conclusion These results indicate that 1) NFκB is a Zn 2+ ‐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. Support or Funding Information American Heart Association ‐ Scientist Development Grant # 16SDG27080009 National Institutes of Health ‐ R21 Exploratory/Development Grant # R21DK119879