Premium
NFkB Mediates Renal Sodium Retention via the Sodium Chloride Cotransporter in Zinc Deficiency‐induced Hypertension
Author(s) -
Murta Cindellynn,
Schindele Dylan,
Wenegieme Tara-Yesomi,
Waite Aston,
Naraine Meagan,
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.s1.01833
Subject(s) - endocrinology , medicine , cotransporter , chemistry , downregulation and upregulation , kidney , sodium , blood pressure , western blot , distal convoluted tubule , kidney disease , urinary system , biochemistry , reabsorption , organic chemistry , gene
Background Zinc deficiency (ZnD) is comorbid with diseases such as kidney disease and diabetes. Individuals in these populations have a higher prevalence of hypertension. Recently, we reported that ZnD promotes hypertension in mice. The blood pressure elevations were accompanied with increased Na + retention via the renal Sodium Chloride Cotransporter (NCC). Although our published results indicate that zinc plays a critical role in blood pressure and NCC regulation, the mechanisms involved were not investigated. Hypothesis Since nuclear factor‐kB (NFκB) mediates ZnD‐induced detrimental effects, we tested the hypothesis that NFκB drives ZnD‐induced NCC upregulation and subsequently renal Na + retention and hypertension. Experimental Design To determine the role of NFκB in ZnD‐induced renal Na + retention and hypertension, adult male C57Bl/6 mice were fed a ZnD diet (5 weeks) followed by administration of the NFκB inhibitor ‐ caffeic acid phenethyl ester (CAPE; 1 week). Systolic blood pressure and urinary Na + concentrations were examined. To examine if NFκB mediates ZnD‐induced NCC upregulation, mouse distal convoluted tubule (mDCT) cells were treated with the zinc chelator N, N, N′, N′‐tetrakis(2‐pyridinylmethyl)‐1,2‐ethanediamine (TPEN) ± CAPE, a NFκB inhibitor. After 24 hours, NCC mRNA and protein expressions, as well as activation, were assessed by qRT‐PCR, Western blot and immunofluorescence, respectively. Results In mice, ZnD promoted hypertension and renal Na + retention. Further, increased NCC expression was accompanied with enhanced NFκB expression in ZnD mice. However, CAPE administration lowered blood pressure and elevated urinary Na + concentrations. In mDCT cells, TPEN‐induced NCC upregulation was prevented by CAPE treatment. Conclusions Together, these results demonstrate that 1) NFκB is a novel NCC regulator and 2) NFκB mediates ZnD‐induced renal Na + retention and hypertension. These novel findings indicate that ZnD drives renal NFκB activation thereby stimulating NCC‐mediated Na + retention and promoting hypertension. Significance This study identifies NFκB as a possible pharmacological target to mitigate hypertension. Support or Funding Information American Heart Association ‐ Scientist Development Grant #16SDG27080009 National Institutes of Health ‐ R21 Exploratory/Development Grant #R21DK119879