Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress

Abstract

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, N-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO Indeed, the activity of the endogenous OO scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO<sup/>.

Association Between Dietary Zinc Intake and Metabolic Syndrome. A Meta-Analysis of Observational Studies

“…Nevertheless, the toxicity of excess zinc intake should not be ignored neither. Excess zinc intake leads to the aggravation of renal function and an increase in systemic blood pressure predominantly through the oxidative stress (54). Moreover, excess dietary zinc intake may have negative impacts on epithelial signaling pathways, barrier function, and luminal ecology in the intestine, which may have long-term consequences on intestinal health (55).…”

Serum zinc concentrations and incident hypertension

“…In addition, zinc deficiency has also been shown to lower the levels of angiotensin-converting enzymes [37] and reduce vasodilation reaction to bradykinin and prostacycline [38]. Finally, rats with an excess intake of zinc demonstrated impaired renal function with a concomitant increase in SBP, resulting from a decrease in the vasodilatory action of nitric oxide (which is known to be involved in the regulation of systemic blood pressure via vascular tone modulation [39]) triggered by superoxide radical-induced oxidative stress [40]. There is a possibility that these findings from animal models may be consistent with that observed in humans; however, further mechanistic studies are required to unravel the pathways involved in the association.…”

Understanding Metal Dynamics Between Cancer Cells and Macrophages: Competition or Synergism?

“…Moreover, as well as zinc oxide (ZnO) nanoparticles, zinc sulfate induces a proinflammatory phenotype in a macrophage cell line and in peritoneal macrophages (Table 1) (31, 35), and this may pave the way for innovative TAM-specific agents able to switch the M2-like phenotype toward a tumorinhibiting M1-like phenotype. On the other hand, excessive zinc supplementation can generate side effects, such as high blood pressure (45). Before starting zinc-based therapy, it would be essential to profile zinc levels in patients and to contextualize them to the molecular phenotype of cancer, histological grading, metastatic potential etc.…”