Metallothionein Protects Against Hg-Induced Nephrotoxicity in Models of Reduced Renal Mass

Abstract

Metallothioneins are low-molecular-weight proteins that are rich in sulfhydryl groups. Consequently, they bind readily to metal ions such as mercury (Hg). Hg is a critical environmental toxicant to which humans are exposed regularly. Individuals with renal insufficiencies, such as those with chronic kidney disease (CKD), may be more susceptible to the effects of Hg, and exposure to Hg enhances the progression of the disease. We hypothesized that metallothionein (MT) acts as an endogenous antioxidant that can reduce the nephrotoxic effects of heavy metals. The effect of MT is significant in patients with reduced renal function, such as those with CKD. To test our hypothesis, we used male and female Wistar rats that underwent uninephrectomy or were sham controls. Animals were allowed to recover for three weeks and were then injected intraperitoneally (i.p.) with saline or zinc (Zn), followed by intravenous (i.v.) injection with HgCl2 (0.5 or 1.25 µmol kg-1). Rats were euthanized 24 h after the Hg injection, and a kidney and liver were harvested. One-half of one kidney was placed in fixative for histological analyses; the remaining renal tissue was frozen immediately in liquid nitrogen for future studies. qPCR and Western blotting confirmed that injecting rats with zinc enhanced the expression of mRNA encoding MT. Expression of mRNA encoding superoxide dismutase and glutamate-cysteine ligase was also measured in the kidney using qPCR to show that MT reduced oxidative stress in these organs. Histological analyses of kidney sections showed significant renal injury in animals injected with saline and exposed to 1.25 µmol HgCl2. Interestingly, renal in corresponding animals injected with zinc demonstrated less nephrotoxicity, suggesting that increased expression of MT protects against Hg-induced nephrotoxicity. Enhanced expression of MT may slow the progression of renal disease in individuals with CKD living in areas contaminated with heavy metals.