Hg(II)-induced renal cytotoxicity: in vitro and in vivo implications for the bioenergetic and oxidative status of mitochondria.
The effects of Hg(II) on bioenergetic and oxidative status of rat renal cortex mitochondria were evaluated both in vitro, and in vivo 1 and 24 h after treatment of animals with 5 mg HgCl2/kg i.p. The parameters assessed were mitochondrial respiration, ATP synthesis and hydrolysis, glutathione content, lipid peroxidation, protein oxidation, and activity of antioxidant enzymes. At low concentration (5 microM) and during a short incubation time, Hg(II) uncoupled oxidative phosphorylation while at slightly higher concentration or longer incubation time the ion impaired the respiratory chain. The rate of ATP synthesis and the phosphorylation potential of mitochondria were depressed, although inhibition of ATP synthesis did not exceed 50%. In vivo, respiration and ATP synthesis were not affected 1 h post-treatment, but were markedly depressed 24 h later. ATP hydrolysis by submitochondrial particle FoF1-ATPase was inhibited (also by no more than 50%) both in vitro, and in vivo 1 and 24 h post-treatment. Hg(II) induced maximum ATPase inhibition at about 1 microM concentration but did not have a strong inhibitory effect in the presence of Triton X-100. Oxidative stress was not observed in mitochondria 1 h post-treatment. However, 24 h later Hg(II) reduced the GSH/GSSG ratio and increased mitochondrial lipid peroxidation and protein oxidation, as well as inhibited GSH-peroxidase and GSSG-reductase activities. These results suggest that the following sequence of events may be involved in Hg(II) toxicity in the kidney: (1) inhibition of FoF1-ATPase, (2) uncoupling of oxidative phosphorylation, (3) oxidative stress-associated impairment of the respiratory chain, and (4) inhibition of ATP synthesis.
Santos
A C
AC
Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Ribeirão Preto, Brasil.
Uyemura
S A
SA
Santos
N A
NA
Mingatto
F E
FE
Curti
C
C
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008627:Mercuric Chloride / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D006180:Proton-Translocating ATPases / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D008627:Mercuric Chloride; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases