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Sodium Chloride Cotransporter Upregulation in Settings of Zinc Deficiency Offers New Insight into Blood Pressure Dysregulation in Chronic Diseases
Author(s) -
Williams Clintoria R.,
Mistry Monisha,
Mallick Rickta,
Mistry Abinash,
Ko Ben,
Gooch Jennifer L.,
Hoover Robert S.
Publication year - 2017
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.31.1_supplement.855.1
Subject(s) - cotransporter , distal convoluted tubule , zinc deficiency (plant disorder) , endocrinology , downregulation and upregulation , in vitro , medicine , chemistry , in vivo , homeostasis , intracellular , blood pressure , sodium , western blot , zinc , kidney , microbiology and biotechnology , reabsorption , biochemistry , biology , organic chemistry , gene
Background Zn 2+ deficiency is a common comorbidity with numerous chronic diseases including type II diabetes and chronic kidney disease. Experimental data show that Zn 2+ deficiency exacerbates hypertension in these settings. Moreover, Zn 2+ deficiency alone may be sufficient to alter blood pressure; however, the mechanisms involved are unknown. Objective The renal distal convoluted tubule sodium chloride cotransporter (NCC) plays a critical role in blood pressure regulation and hypertension. The objective of this study was to determine if Zn 2+ deficiency alters NCC expression and/or activation in vivo and in vitro . Experimental Design To this end, WT mice were pair‐fed a diet with 50 ppm Zn 2+ (Zn 2+ adequate [ZnA]) or a diet with 1 ppm Zn 2+ (Zn 2+ deficient [ZnD]) for 6 weeks. To reduce intracellular Zn 2+ levels in vitro , WT mouse distal convoluted tubular (mDCT‐15) cells were cultured in 1 nM N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine (TPEN)‐ or vehicle (DMSO)‐containing medium for 24 hours. To replete intracellular Zn 2+ , TPEN‐exposed cells were then cultured in 1 nM Zn 2+ ‐supplemented medium for 24 hours. NCC mRNA and protein expression were examined in vivo and in vitro via qRT‐PCR, western blot and immunohistochemistry. NCC activation was assessed by cellular localization (via biotinylation and immunofluorescence) and Na + uptake activity (via thiazide‐sensitive assays). Results In ZnD mice, NCC protein expression is increased in DCT cells compared to mice receiving a ZnA‐diet. In the in vitro model of Zn 2+ deficiency, Zn 2+ chelation with TPEN stimulates NCC mRNA and protein expression compared to vehicle‐treated cells. Furthermore, TPEN promotes NCC surface localization and Na + uptake activity. Notably, restoration of intracellular Zn 2+ levels by supplementation reverses TPEN effects on NCC. Conclusions Our findings indicate that NCC is a Zn 2+ ‐sensitive transporter and is upregulated in settings of Zn 2+ deficiency. Significance This sodium transporter represents a novel mechanism by which Zn 2+ deficiency may alter blood pressure and contribute to hypertension in chronic disease settings. Future experiments are needed to determine what additional factors are involved in Zn 2+ deficiency‐induced upregulation of NCC and to test if protecting NCC from Zn 2+ regulation has a positive impact on hypertension.