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Acute renal failure potentiates methylmalonate-induced oxidative stress in brain and kidney of rats
P F Schuck1, L Alves, L F Pettenuzzo
1Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma , SC , Brazil. patricia.schuck@pq.cnpq.br
Abstract:
Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. The disease is clinically characterized by progressive neurological deterioration and kidney failure, whose pathophysiology is still unclear. In the present work we investigated the effects of acute MMA administration on various parameters of oxidative stress in cerebral cortex and kidney of young rats, as well as the influence of acute renal failure on MMA-elicited effects on these parameters. Acute renal failure was induced by gentamicin, an aminoglycoside antibiotic whose utilization over prolonged periods causes nephrotoxicity. The administration of gentamicin alone increased carbonyl content and inhibited superoxide dismutase (SOD) activity in cerebral cortex, as well as increased thiobarbituric acid-reactive substances (TBA-RS) and sulfhydryl levels and diminished glutathione peroxidase activity in kidney. On the other hand, MMA administration increased TBA-RS levels in cerebral cortex and decreased SOD activity in kidney. Furthermore, the simultaneous administration of MMA and gentamicin to the rats provoked an augment in TBA-RS levels and superoxide generation in cerebral cortex and in TBA-RS, carbonyl and sulfhydryl levels in kidney, while diminished SOD activity in both studied tissues. Finally, nitrate/nitrite content, reduced glutathione levels, 2',7'-dihydrodichlorofluorescein oxidation and catalase activity were not affected by this animal treatment in either tissue. In conclusion, our present data are in line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on oxidative stress parameters in brain and peripheral tissues.
Insights
Methylmalonic acid (MMA) accumulation causes methylmalonic acidemia, leading to neurological and kidney damage. This study shows MMA acts as a toxin in rat brain and kidneys, with kidney injury worsening its effects.
Area of Science:
- Biochemistry
- Toxicology
- Neuroscience
Background:
- Methylmalonic acidemia is characterized by tissue methylmalonic acid (MMA) accumulation, leading to neurological deterioration and kidney failure.
- The precise pathophysiology of these complications remains unclear.
Purpose of the Study:
- To investigate the effects of acute MMA administration on oxidative stress parameters in the rat cerebral cortex and kidney.
- To determine how acute renal failure influences MMA-induced oxidative stress.
Main Methods:
- Acute renal failure was induced using gentamicin.
- Rats received MMA, gentamicin, or both.
- Oxidative stress markers (TBA-RS, carbonyl, sulfhydryl, SOD activity, superoxide generation) were measured in cerebral cortex and kidney.
Main Results:
- Gentamicin alone induced oxidative stress in the brain and kidney.
- MMA administration alone increased oxidative stress markers in the cerebral cortex and kidney.
- Combined MMA and gentamicin administration exacerbated oxidative stress in both tissues, notably increasing TBA-RS and superoxide generation in the brain and TBA-RS, carbonyl, and sulfhydryl levels in the kidney.
Conclusions:
- MMA exhibits toxic effects on the brain and kidneys in rats.
- Renal injury potentiates MMA's toxicity on oxidative stress parameters in both brain and kidney tissues.
