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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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References

  1. Kon S, Konta T, Ichikawa K, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Kasahara M, Shibagaki Y, Iseki K, Moriyama T, Kondo M, Watanabe T. Association between renal function and cardiovascular and all-cause mortality in the community-based elderly population: results from the specific health check and guidance program in Japan. Clin Exp Nephrol. 2018;22:346–52.

    Article  PubMed  Google Scholar 

  2. Marreiros C, Viegas C, Simes D. Targeting a silent disease: vascular calcification in chronic kidney disease. Int J Mol Sci. 2022;23:16114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int. 2000;57:1803–17.

    Article  CAS  PubMed  Google Scholar 

  4. Takata T, Isomoto H. Pleiotropic effects of sodium-glucose Cotransporter-2 inhibitors: renoprotective mechanisms beyond glycemic control. Int J Mol Sci. 2021;22:4374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Milik A, Chapter HE. Management of progression and complications of CKD. Kidney Int Suppl. 2013;3:73–90.

    Article  Google Scholar 

  6. Cortinovis M, Ruggenenti P, Remuzzi G. Progression, remission and regression of chronic renal diseases. Nephron. 2016;134:20–4.

    Article  CAS  PubMed  Google Scholar 

  7. Ohno S, Ishii A, Yanagita M, Yokoi H. Calcium channel blocker in patients with chronic kidney disease. Clin Exp Nephrol. 2022;26:207–15.

    Article  CAS  PubMed  Google Scholar 

  8. Bourque G, Hiremath S. Rethinking resistant hypertension. J Clin Med. 2022;11:1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maaliki D, Itani MM, Itani HA. Pathophysiology and genetics of salt-sensitive hypertension. Front Physiol. 2022;13:1001434.

    Article  PubMed  PubMed Central  Google Scholar 

  10. He FJ, MacGregor GA. How far should salt intake be reduced? Hypertension. 2003;42:1093–9.

    Article  CAS  PubMed  Google Scholar 

  11. Guyton AC. Blood pressure control–special role of the kidneys and body fluids. Science. 1991;252:1813–6.

    Article  CAS  PubMed  Google Scholar 

  12. Trepiccione F, Zacchia M, Capasso G. The role of the kidney in salt-sensitive hypertension. Clin Exp Nephrol. 2021;16:68–72.

    Article  Google Scholar 

  13. Nanamatsu A, Mori T, Ando F, Furusho T, Mandai S, Susa K, Sohara E, Rai T, Uchida S. Vasopressin induces urinary uromodulin secretion by activating PKA (protein kinase A). Hypertension. 2021;77:1953–63.

    Article  CAS  PubMed  Google Scholar 

  14. Takata T, Hamada S, Mae Y, Iyama T, Ogihara R, Seno M, Nakamura K, Takata M, Sugihara T, Isomoto H. Uromodulin regulates murine aquaporin-2 activity via thick ascending limb-collecting duct cross-talk during water deprivation. Int J Mol Sci. 2022;23:9410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Coffman TM, Crowley SD. Kidney in hypertension: guyton redux. Hypertension. 2008;51:811–6.

    Article  CAS  PubMed  Google Scholar 

  16. Bovée DM, Cuevas CA, Zietse R, Danser AHJ, Mirabito Colafella KM, Hoorn EJ. Salt-sensitive hypertension in chronic kidney disease: distal tubular mechanisms. Am J Physiol Ren Physiol. 2020;319:F729–45.

    Article  Google Scholar 

  17. Takata T, Isomoto H. The versatile role of uromodulin in renal homeostasis and its relevance in chronic kidney disease. InternMed. 2024;63:17–23. https://doi.org/10.2169/internalmedicine.1342-22.

    Article  CAS  Google Scholar 

  18. Kambe T, Tsuji T, Hashimoto A, Itsumura N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol Rev. 2015;95:749–84.

    Article  CAS  PubMed  Google Scholar 

  19. Kambe T, Hashimoto A, Fujimoto S. Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell Mol Life Sci. 2014;71:3281–95.

    Article  CAS  PubMed  Google Scholar 

  20. Franceschini N, Chasman DI, Cooper-DeHoff RM, Arnett DK. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies. Curr Hypertens Rep. 2014;16:461.

    Article  PubMed  PubMed Central  Google Scholar 

  21. International Consortium for Blood Pressure Genome-Wide Association Studies, Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478:103–9.

    Article  Google Scholar 

  22. Kimura T, Kambe T. The functions of metallothionein and ZIP and ZnT transporters: an overview and perspective. Int J Mol Sci. 2016;17:336.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hu R, McDonough AA, Layton AT. Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis. Am J Physiol Ren Physiol. 2019;317:F1462–74.

    Article  CAS  Google Scholar 

  24. Gonzalez-Vicente A, Hong NJ, Yang N, Cabral PD, Berthiaume JM, Dominici FP, Garvin JL. Dietary fructose increases the sensitivity of proximal tubules to angiotensin II in rats fed high-salt diets. Nutrients. 2018;10:1244.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Olinger E, Lake J, Sheehan S, Schiano G, Takata T, Tokonami N, Debaix H, Consolato F, Rampoldi L, Korstanje R, Devuyst O. Hepsin-mediated processing of uromodulin is crucial for salt-sensitivity and thick ascending limb homeostasis. Sci Rep. 2019;9:12287.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Takata T, Munemura C, Fukui T, Fukuda S, Murawaki Y. Influence of olmesartan on sirtuin 1 mRNA expression in 5/6 nephrectomized spontaneously hypertensive rats. Yonago Acta Med. 2015;58:63–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hosokawa K, Takata T, Sugihara T, Matono T, Koda M, Kanda T, Taniguchi S, Ida A, Mae Y, Yamamoto M, Iyama T, Fukuda S, Isomoto H. Ipragliflozin ameliorates endoplasmic reticulum stress and apoptosis through preventing ectopic lipiddeposition in renal tubules. Int J Mol Sci. 2019;21:190.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tokonami N, Takata T, Beyeler J, Ehrbar I, Yoshifuji A, Christensen EI, Loffing J, Devuyst O, Olinger EG. Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC. Kidney Int. 2018;94:701–15.

    Article  CAS  PubMed  Google Scholar 

  29. Lewis S, Chen L, Raghuram V, Khundmiri S, Chou CL, Yang CR, Knepper MA. “SLC-omics” of the kidney: solute transporters along the nephron. Am J Physiol Cell Physiol. 2021;321:C507-518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Williams CR, Mistry M, Cheriyan AM, Williams JM, Naraine MK, Ellis CL, Mallick R, Mistry AC, Gooch JL, Ko B, Cai H, Hoover RS. Zinc deficiency induces hypertension by promoting renal Na+ reabsorption. Am J Physiol Ren Physiol. 2019;316:F646–53.

    Article  CAS  Google Scholar 

  31. Feng HL, Chen YH, Jeng SS. Effect of zinc supplementation on renal anemia in 5/6-nephrectomized rats and a comparison with treatment with recombinant human erythropoietin. Int J Mol Sci. 2019;20:4985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tubek S. Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension. Biol Trace Elem Res. 2007;117:39–51.

    Article  CAS  PubMed  Google Scholar 

  33. Tahir F, Majid Z, Qadar LT. Zinc deficiency: an independent risk factor for high blood pressure. J Pak Med Assoc. 2019;69:1578.

    PubMed  Google Scholar 

  34. Ozyildirim S, Baltaci SB. Cardiovascular diseases and zinc. Biol Trace Elem Res. 2023;201:1615–26.

    Article  CAS  PubMed  Google Scholar 

  35. Ume AC, Wenegieme TY, Adams DN, Adesina SE, Williams CR. Zinc deficiency: a potential hidden driver of thedetrimental cycle of chronic kidney disease and hypertension. Kidney. 2023;360(4):398–404.

    Article  Google Scholar 

  36. Bergomi M, Rovesti S, Vinceti M, Vivoli R, Caselgrandi E, Vivoli G. Zinc and copper status and blood pressure. J Trace Elem Med Biol. 1997;11:166–9.

    Article  CAS  PubMed  Google Scholar 

  37. Medeiros DM, Brown BJ. Blood pressure in young adults as influenced by copper and zinc intake. Biol Trace Elem Res. 1983;5:165–74.

    Article  CAS  PubMed  Google Scholar 

  38. Kim J. Dietary zinc intake is inversely associated with systolic blood pressure in young obese women. Nutr Res Pract. 2013;7:380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kunutsor SK, Laukkanen JA. Serum zinc concentrations and incident hypertension: new findings from a population-based cohort study. J Hypertens. 2016;34:1055–61.

    Article  CAS  PubMed  Google Scholar 

  40. Sato M, Yanagisawa H, Nojima Y, Tamura J, Wada O. Zn deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase. Clin Exp Hypertens. 2002;24:355–70.

    Article  CAS  PubMed  Google Scholar 

  41. Dimitrova AA, Strashimirov D, Betova T, Russeva A, Alexandrova M. Zinc content in the diet affects the activity of Cu/ZnSOD, lipid peroxidation and lipid profile of spontaneously hypertensive rats. Acta Biol Hung. 2008;59:305–14.

    Article  PubMed  Google Scholar 

  42. Hatanaka M, Kaimori JY, Yamamoto S, Matsui I, Hamano T, Takabatake Y, Ecelbarger CM, Takahara S, Isaka Y, Rakugi H. Azilsartan improves salt sensitivity by modulating the proximal tubular Na+-H+ exchanger-3 in mice. PLoS One. 2016;11:

    Article  PubMed  PubMed Central  Google Scholar 

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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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  2. Tomoaki Takata
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  3. Hinako Hanada
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  4. Sosuke Taniguchi
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  8. Tsutomu Kanda
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  9. Hajime Isomoto
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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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Conflict of interest

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 (2024). https://doi.org/10.1007/s10157-024-02478-7

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