Zinc deficiency induces hypertension by promoting renal Na⁺ reabsorption

Abstract

Zn2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn2+ in BP regulation, adult mice were fed a Zn2+-adequate (ZnA) or a Zn2+-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na+-Cl− cotransporter (NCC) inhibitor. To reduce intracellular Zn2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N′,N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn2+ chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn2+, TPEN-exposed cells were then cultured in Zn2+-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na+ excretion and NCC upregulation. These effects were reversed in Zn2+-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na+ uptake activity. Zn2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na+ handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.

Maternal Serum Zinc Level and Pre-eclampsia Risk in African Women: a Systematic Review and Meta-analysis

“…In this review, the serum Zn level was decreased in pre-eclamptic women than normal controls; the mechanism how Zn deficiency causes pre-eclampsia is not clearly understood. However, animal model studies suggested that Zn deficiency may induce high blood pressure by promoting sodium reabsorption by increasing Na + -Cl − cotransporter expression [44]. Zn deficiency in prenatal and postnatal rats induces blood pressure derangement accompanied by cardiovascular and renal morphological and functional changes [45].…”

Association of Zinc Deficiency with Development of CVD Events in Patients with CKD

“…Additionally, in spontaneous hypertension-prone rats, dietary zinc restriction exacerbated systolic blood pressure [ 102 ], whereas zinc supplementation attenuated blood pressure response [ 103 ]. Of interest, Williams et al revealed a possible mechanism of zinc related to blood pressure regulation, as an Na + -Cl − cotransporter (NCC) was found to be a zinc-regulated transporter upregulated in mice with zinc deficiency, and NCC upregulation contributed to increased blood pressure by stimulating renal sodium reabsorption [ 104 ]. In human studies, it has been reported that populations with low dietary zinc intake have a high prevalence of hypertension, and a possible inverse correlation between zinc levels and blood pressure has also been noted [ 105 , 106 ].…”

Selenium, copper, zinc and hypertension: an analysis of the National Health and Nutrition Examination Survey (2011–2016)

“…However, inverse correlations of blood pressure and serum zinc have also been observed [20]. A recently published article has implicated zinc deficiency to hypertension in animal models [21]. In another study, excessive zinc intake elevated systemic blood pressure levels in animal models and was presumably associated with the oxidative stress [22].…”