Early Morphological and Biochemical Changes During 2-Br-(diglutathion-S-yl)hydroquinone-Induced Nephrotoxicity

M. I. Rivera, T. W. Jones, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Early subcellular targets of 2-Br-(diglutathion-S-yl)hydroquinone (2-Br-(diGSyl)HQ)-mediated nephrotoxicity were investigated by morphological and biochemical criteria. After treatment of male Fischer 344 rats with 2-Br-(diGSyl)HQ (30 μmol/ kg), proximal tubular morphology was examined by electron microscopy. Changes in the plasma membrane, nuclei, and endoplasmic reticulum were observed within 30 min of 2-Br-(di-GSyl)HQ administration. These changes consisted of loss of the brush border membrane, margination of heterochromatin, and reorganization of the endoplasmic reticulum into discrete aggregates. The desquamation of the brush border membrane into the tubular lumen corresponded with the rapid excretion of γ-glutamyl transpeptidase and alkaline phosphatase in urine. As the injury developed, cell swelling with loss of cytosolic density and loss of chromatin staining was observed, and between 2 and 4 hr the nuclei underwent extensive karyorrhexis and karyolysis. Agarose gel electrophoresis of DNA isolated from the corticomedullary junction at 4 hr exhibited extensive fragmentation, which was random in nature. Mitochondria assumed a condensed configuration 2 hr after 2-Br-(diGSyl)HQ administration, but this was not followed by high-amplitude swelling prior to cell death and necrosis. Biochemical assessment of mitochondria, isolated from 2-Br-(diGSyl)HQ-treated rats at 2 hr, exhibited a significant (20%) decrease in respiratory control ratios (RCR), a consequence of an increase in State 4 respiration. At later time points (8 hr) State 4 respiration returned to control values, but the respiratory control ratio (RCR) remained significantly depressed due to decreases in State 3 respiration. At this time blood urea nitrogen concentrations were significantly elevated (41 ± 3, mean ± SD, n = 10). The data suggest that the plasma membrane and the nucleus are early targets of 2-Br-(diGSyl)HQ-induced cytotoxicity, and that alterations in mitochondrial structure and respiratory function occur following the initial injury.

Original languageEnglish (US)
Pages (from-to)239-250
Number of pages12
JournalToxicology and Applied Pharmacology
Volume128
Issue number2
DOIs
StatePublished - Oct 1994
Externally publishedYes

Fingerprint

Respiration
Mitochondria
Brushes
Cell membranes
Microvilli
Endoplasmic Reticulum
Swelling
Rats
Cell Membrane
Membranes
Heterochromatin
gamma-Glutamyltransferase
Agar Gel Electrophoresis
Blood Urea Nitrogen
Inbred F344 Rats
Wounds and Injuries
Cell death
Cytotoxicity
Electrophoresis
Sepharose

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Early Morphological and Biochemical Changes During 2-Br-(diglutathion-S-yl)hydroquinone-Induced Nephrotoxicity. / Rivera, M. I.; Jones, T. W.; Lau, Serrine; Monks, Terrence.

In: Toxicology and Applied Pharmacology, Vol. 128, No. 2, 10.1994, p. 239-250.

Research output: Contribution to journalArticle

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abstract = "Early subcellular targets of 2-Br-(diglutathion-S-yl)hydroquinone (2-Br-(diGSyl)HQ)-mediated nephrotoxicity were investigated by morphological and biochemical criteria. After treatment of male Fischer 344 rats with 2-Br-(diGSyl)HQ (30 μmol/ kg), proximal tubular morphology was examined by electron microscopy. Changes in the plasma membrane, nuclei, and endoplasmic reticulum were observed within 30 min of 2-Br-(di-GSyl)HQ administration. These changes consisted of loss of the brush border membrane, margination of heterochromatin, and reorganization of the endoplasmic reticulum into discrete aggregates. The desquamation of the brush border membrane into the tubular lumen corresponded with the rapid excretion of γ-glutamyl transpeptidase and alkaline phosphatase in urine. As the injury developed, cell swelling with loss of cytosolic density and loss of chromatin staining was observed, and between 2 and 4 hr the nuclei underwent extensive karyorrhexis and karyolysis. Agarose gel electrophoresis of DNA isolated from the corticomedullary junction at 4 hr exhibited extensive fragmentation, which was random in nature. Mitochondria assumed a condensed configuration 2 hr after 2-Br-(diGSyl)HQ administration, but this was not followed by high-amplitude swelling prior to cell death and necrosis. Biochemical assessment of mitochondria, isolated from 2-Br-(diGSyl)HQ-treated rats at 2 hr, exhibited a significant (20{\%}) decrease in respiratory control ratios (RCR), a consequence of an increase in State 4 respiration. At later time points (8 hr) State 4 respiration returned to control values, but the respiratory control ratio (RCR) remained significantly depressed due to decreases in State 3 respiration. At this time blood urea nitrogen concentrations were significantly elevated (41 ± 3, mean ± SD, n = 10). The data suggest that the plasma membrane and the nucleus are early targets of 2-Br-(diGSyl)HQ-induced cytotoxicity, and that alterations in mitochondrial structure and respiratory function occur following the initial injury.",
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