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Zinc deficiency induces hypertension by paradoxically amplifying salt sensitivity under high salt intake in mice

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Abstract

Background

Hypertension is one of the major etiologies that cause chronic kidney disease (CKD) and can exacerbate kidney dysfunction. Zinc is an essential trace element playing a role in blood pressure regulation, and zinc deficiency, a common comorbidity in patients with CKD, can cause hypertension. However, the precise mechanism underlying zinc deficiency-induced hypertension is unknown. Sodium (Na+) retention due to inappropriate Na+ reabsorption in the renal tubule is the principal pathophysiology of hypertension. Therefore, this study aimed to investigate the association between zinc deficiency and salt sensitivity.

Methods

Adult mice were fed a zinc-adequate (ZnA) or zinc-deficient (ZnD) diet combined with/without high salt in drinking water (HS) for 4 weeks (n = 6 each). Changes in blood pressure, urinary sodium excretion, and the expressions of the proximal tubular Na+ transporter, Na+/H+ exchanger 3 (NHE3), which mostly contributes to filtered Na+ reabsorption and the downstream Na+–Cl− transporter (NCC) were analyzed.

Results

Urinary Na+ excretion significantly increased in ZnD mice, indicating that zinc deficiency causes natriuresis. NHE3 expressions were significantly suppressed, whereas NCC was upregulated in ZnD mice. Interestingly, the combination of high salt and ZnD diet (HS-ZnD) reversed the urinary Na+ loss. The NCC remained activated and NHE3 expressions paradoxically increased in HS-ZnD mice compared with those fed the combination of high salt and ZnA diet. In addition, blood pressure significantly increased only in HS-ZnD mice.

Conclusion

The combination of zinc deficiency and high salt causes hypertension. Zinc is associated with salt-sensitivity, potentially through NHE3 and NCC regulation.

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Author information

Authors and Affiliations

  1. Division of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Nishi-cho 36-1, Yonago, Tottori, 683-8504, Japan

    Marie Yamamoto, Tomoaki Takata, Hinako Hanada, Sosuke Taniguchi, Shintaro Hamada, Yukari Mae, Takuji Iyama, Tsutomu Kanda & Hajime Isomoto

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  1. Marie Yamamoto
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Contributions

Conceptualization: Marie Yamamoto, Tomoaki Takata Hinako Hanada, Sosuke Taniguchi, Shintaro Hamada, Yukari Mae, and Takuji Iyama; Formal analysis and investigation: Marie Yamamoto, Tomoaki Takata, Takuji Iyama, and Tsutomu Kanda; Writing—original draft preparation: Marie Yamamoto; Writing—review and editing: Tomoaki Takata; Supervision; Hajime Isomoto. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tomoaki Takata.

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All the authors have declared no competing interest.

Ethical approval

This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Approval was granted by the Ethics of Animal Experiments of the Tottori University (19-Y-31).

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Yamamoto, M., Takata, T., Hanada, H. et al. Zinc deficiency induces hypertension by paradoxically amplifying salt sensitivity under high salt intake in mice. Clin Exp Nephrol 28, 728–739 (2024). https://doi.org/10.1007/s10157-024-02478-7

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  • DOI: https://doi.org/10.1007/s10157-024-02478-7

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