Causes and Consequences of Zinc Dyshomeostasis in Rats With Chronic Aldosteronism

Abstract

Iterations in Ca 2+ and Mg 2+ balance accompany aldosteronism (inappropriate for dietary Na + intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined: 1) the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO 3 − excretion; 2) assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn 2+ ] i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress; and 3) monitor oxidative stress and cardiac pathology in response to ZnSO 4 supplement (40 mg/day). Compared to controls, at 4 wks ALDOST we found: an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; a rise in cardiac Zn including increased [Zn 2+ ] i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91 phox , coupled with oxidative stress in plasma and urine; and ZnSO 4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO 4 attenuated cardiomyocyte necrosis, however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contribute to cardiac pathology.

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…We found increased cytosolic free [Zn 2+ ] i in cardiac myocytes and total [Zn 2+ ] m concentration in the mitochondria. 62 The rise in cardiomyocyte [Zn 2+ ] i was facilitated by the increased expression of membranous Zn 2+ transporters. Increased [Zn 2+ ] i serves to augment the antioxidant defenses of cardiomyocytes, including their upregulation of MT-1 and activation of metal-responsive transcription factor-1, which encodes genes related to various antioxidant defenses, such as Cu/Zn-SOD, MT-1 and glutathione synthase.…”

“…We found increased Ca 2+ levels in the myocardium and PBMC during pre-clinical, clinical and pathological stages, accompanied by biomarker evidence of oxidative stress that included increased levels of malondialdehyde and 8-isoprostane in the heart and increased H 2 O 2 production by PBMC. 14,62,64,65 Metabolic studies accounted for the marked increase in urinary and fecal excretion of Ca 2+ and Mg 2+ during ALDOST, which leads to plasma-ionized hypocalcemia and hypomagnesemia. The calciumsensing receptor of the parathyroid glands, in turn, responds to hypocalcemia with increased secretion of PTH.…”

“…13,[59][60][61][62] This includes: the presence of 3-nitrotyrosine, a byproduct of the reaction involving superoxide and nitric oxide; an activation of the gp91 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase found in inflammatory cells invading the injured myocardium that contributes to superoxide generation; upregulated redox-sensitive nuclear transcription factor-kB and a proinflammatory gene cascade it regulates that includes intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-a; and increased tissue levels of 8-isoprostane and malondialdehyde, biomarkers of lipid peroxidation. 13,62 There is also considerable evidence of oxidative stress in blood and urine consistent with the systemic nature of an altered redox state during chronic aldosteronism.…”

“…86 The hyperzincuria seen with ALDOST is related to urinary acidification, which contributes to the consequent metabolic alkalosis of aldosteronism. 62 Also contributory to hypozincemia is a coordinated selective translocation of Zn 2+ to the sites of tissue injury, facilitated by corresponding upregulation of a Zn 2+ -binding protein, metallothionein (MT)-1 in targeted tissues. 62,86 We also used 65 Zn to systematically monitor Zn 2+ kinetics during 1 and 4 weeks of ALDOST.…”

“…62 Also contributory to hypozincemia is a coordinated selective translocation of Zn 2+ to the sites of tissue injury, facilitated by corresponding upregulation of a Zn 2+ -binding protein, metallothionein (MT)-1 in targeted tissues. 62,86 We also used 65 Zn to systematically monitor Zn 2+ kinetics during 1 and 4 weeks of ALDOST. A simultaneous fall in plasma 65 Zn, and a selective accumulation of 65 Zn, was found at sites of injury that included its translocation to freshly incised skin at week 1 caused by osmotic minipump implantation, as well as the injured heart and kidneys at week 4.…”