Premium
NFkB Mediates Renal Sodium Retention via the Sodium Chloride Cotransporter in Zinc Deficiency‐Induced Hypertension
Author(s) -
Murta Cindellynn,
Schindele Dylan,
Naraine Meagan,
Wenegieme TaraYesomi,
Waite Aston,
Sonner Martha,
Williams Clintoria
Publication year - 2021
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.2021.35.s1.02972
Subject(s) - endocrinology , cotransporter , downregulation and upregulation , medicine , chemistry , kidney , blood pressure , sodium , western blot , kidney disease , urinary system , biochemistry , 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 (NFkB) mediates ZnD‐induced detrimental effects, we tested the hypothesis that NFκB drives ZnD‐induced NCC upregulation and subsequently 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 NFkB 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 NFkB 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) NFkB is a novel NCC regulator and 2) NFkB mediates ZnD‐induced renal Na+ retention and hypertension. These novel findings indicate that ZnD drives renal NFkB activation thereby stimulating NCC‐mediated Na+ retention and promoting hypertension. Significance : This study identifies NFkB as a possible pharmacological target to mitigate hypertension.