Studies on the pathophysiology of acute renal failure - IV. Protective effect of dithiothreitol following administration of mercuric chloride in the rat

J. L. Barnes, E. M. McDowell, J. S. McNeil, W. Flamenbaum, B. F. Trump

Research output: Contribution to journalArticle

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Abstract

Studies were undertaken to investigate the effect of dithiothreitol (DTT), an agent capable of chelating heavy metals, on mercuric chloride (HgCl2)-induced acute renal failure (ARF) in rats. The rats were divided into four groups: Control; HgCl2 (4 mg/kg)-alone; DTT (15.4 mg/kg)-alone; and HgCl2 followed 30 min later by DTT (HgCl2 + DTT). Kidneys were studied by light and electron microscopy and histochemical enzyme analysis at 1, 3, 6, 12, 24 and 48 h following treatment. In addition, renal function was monitored at 6, 12, 24 and 48 h. Functionally, HgCl2-alone induced a progressive non-oliguric form of ARF characterized by increased fractional excretion of sodium (FENa+), a reduction in glomerular filtration rate (GFR) and azotemia, apparent by 12 h and continuing throughout the course of study. Administration of HgCl2 + DTT ameliorated the development of ARF whereas DTT, administered by itself, produced no functional abnormality. Administration of HgCl2-alone caused dispersion of cytoplasmic ribosomes at 1 h and 3 h. Also, a reduction in plasma membrane marker enzyme activities (alkaline phosphatase and 5′-nucleotidase), occurred at 1 h, particularly in the pars convoluta. At 6, 12, 24 and 48 h morphological changes in the first portion of the pars convoluta (P1) tended to be reversible. The injury which occurred in the more terminal portions of the pars convoluta (P2) was sublethal in some animals but progressed at the later time intervals to advanced irreversible cell injury followed by necrosis in others. Activity of all enzymes studied returned or remained at control levels at 3 h. However, activities of all enzymes studied, including acid phosphatase and succinate dehydrogenase, were reduced throughout P1 and P2 at 6, 12, 24 and 48 h. By 24 and 48 h, all pars recta (P3) tubules were necrotic and enzyme activities were minimal. Administration of HgCl2 + DTT produced similar but less severe lesions at 1 h as did HgCl2-alone. However, a protective effect (morphological and enzymatic) was evident at 3 h and during the remainder of the study, when virtually no morphological or substantial enzymatic changes occurred in P1 or P2. Nevertheless, by 48 h, extensive necrosis had developed in P3 of HgCl2 + DTT treated rats as in animals treated with HgCl2-alone. DTT when administered alone produced no morphological or enzymatic abnormalities. The results of this study support the hypothesis that a structural-functional correlation exists between the progression of proximal convoluted tubular injury and the development of HgCl2-induced ARF, which is unrelated to necrosis in the pars recta. According to this hypothesis, HgCl2-induced alterations in proximal tubular handling of Na+ and Cl- lead to an augmentation of a tubulo-glomerular feedback mechanism involving the renin-angiotensin system. This results in vasoconstriction of the afferent arteriole and subsequent filtration failure. DTT ameliorates HgCl2-induced ARF by altering the effect of the heavy metal on Na+ and Cl- transport functions and the subsequent initiation of such a feedback mechanism.

Original languageEnglish (US)
Pages (from-to)201-232
Number of pages32
JournalVirchows Archiv B Cell Pathology Including Molecular Pathology
Volume32
Issue number1
DOIs
StatePublished - Dec 1980
Externally publishedYes

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Mercuric Chloride
Dithiothreitol
Acute Kidney Injury
Enzymes
Necrosis
Heavy Metals
Rectum
Wounds and Injuries
Azotemia
Kidney
5'-Nucleotidase
Succinate Dehydrogenase
Arterioles
Renin-Angiotensin System
Chelating Agents
Acid Phosphatase
Vasoconstriction
Glomerular Filtration Rate
Ribosomes

Keywords

  • Acute renal failure
  • Dithiothreitol
  • Enzymes
  • Mercuric chloride
  • Proximal tubule

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Studies on the pathophysiology of acute renal failure - IV. Protective effect of dithiothreitol following administration of mercuric chloride in the rat. / Barnes, J. L.; McDowell, E. M.; McNeil, J. S.; Flamenbaum, W.; Trump, B. F.

In: Virchows Archiv B Cell Pathology Including Molecular Pathology, Vol. 32, No. 1, 12.1980, p. 201-232.

Research output: Contribution to journalArticle

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N2 - Studies were undertaken to investigate the effect of dithiothreitol (DTT), an agent capable of chelating heavy metals, on mercuric chloride (HgCl2)-induced acute renal failure (ARF) in rats. The rats were divided into four groups: Control; HgCl2 (4 mg/kg)-alone; DTT (15.4 mg/kg)-alone; and HgCl2 followed 30 min later by DTT (HgCl2 + DTT). Kidneys were studied by light and electron microscopy and histochemical enzyme analysis at 1, 3, 6, 12, 24 and 48 h following treatment. In addition, renal function was monitored at 6, 12, 24 and 48 h. Functionally, HgCl2-alone induced a progressive non-oliguric form of ARF characterized by increased fractional excretion of sodium (FENa+), a reduction in glomerular filtration rate (GFR) and azotemia, apparent by 12 h and continuing throughout the course of study. Administration of HgCl2 + DTT ameliorated the development of ARF whereas DTT, administered by itself, produced no functional abnormality. Administration of HgCl2-alone caused dispersion of cytoplasmic ribosomes at 1 h and 3 h. Also, a reduction in plasma membrane marker enzyme activities (alkaline phosphatase and 5′-nucleotidase), occurred at 1 h, particularly in the pars convoluta. At 6, 12, 24 and 48 h morphological changes in the first portion of the pars convoluta (P1) tended to be reversible. The injury which occurred in the more terminal portions of the pars convoluta (P2) was sublethal in some animals but progressed at the later time intervals to advanced irreversible cell injury followed by necrosis in others. Activity of all enzymes studied returned or remained at control levels at 3 h. However, activities of all enzymes studied, including acid phosphatase and succinate dehydrogenase, were reduced throughout P1 and P2 at 6, 12, 24 and 48 h. By 24 and 48 h, all pars recta (P3) tubules were necrotic and enzyme activities were minimal. Administration of HgCl2 + DTT produced similar but less severe lesions at 1 h as did HgCl2-alone. However, a protective effect (morphological and enzymatic) was evident at 3 h and during the remainder of the study, when virtually no morphological or substantial enzymatic changes occurred in P1 or P2. Nevertheless, by 48 h, extensive necrosis had developed in P3 of HgCl2 + DTT treated rats as in animals treated with HgCl2-alone. DTT when administered alone produced no morphological or enzymatic abnormalities. The results of this study support the hypothesis that a structural-functional correlation exists between the progression of proximal convoluted tubular injury and the development of HgCl2-induced ARF, which is unrelated to necrosis in the pars recta. According to this hypothesis, HgCl2-induced alterations in proximal tubular handling of Na+ and Cl- lead to an augmentation of a tubulo-glomerular feedback mechanism involving the renin-angiotensin system. This results in vasoconstriction of the afferent arteriole and subsequent filtration failure. DTT ameliorates HgCl2-induced ARF by altering the effect of the heavy metal on Na+ and Cl- transport functions and the subsequent initiation of such a feedback mechanism.

AB - Studies were undertaken to investigate the effect of dithiothreitol (DTT), an agent capable of chelating heavy metals, on mercuric chloride (HgCl2)-induced acute renal failure (ARF) in rats. The rats were divided into four groups: Control; HgCl2 (4 mg/kg)-alone; DTT (15.4 mg/kg)-alone; and HgCl2 followed 30 min later by DTT (HgCl2 + DTT). Kidneys were studied by light and electron microscopy and histochemical enzyme analysis at 1, 3, 6, 12, 24 and 48 h following treatment. In addition, renal function was monitored at 6, 12, 24 and 48 h. Functionally, HgCl2-alone induced a progressive non-oliguric form of ARF characterized by increased fractional excretion of sodium (FENa+), a reduction in glomerular filtration rate (GFR) and azotemia, apparent by 12 h and continuing throughout the course of study. Administration of HgCl2 + DTT ameliorated the development of ARF whereas DTT, administered by itself, produced no functional abnormality. Administration of HgCl2-alone caused dispersion of cytoplasmic ribosomes at 1 h and 3 h. Also, a reduction in plasma membrane marker enzyme activities (alkaline phosphatase and 5′-nucleotidase), occurred at 1 h, particularly in the pars convoluta. At 6, 12, 24 and 48 h morphological changes in the first portion of the pars convoluta (P1) tended to be reversible. The injury which occurred in the more terminal portions of the pars convoluta (P2) was sublethal in some animals but progressed at the later time intervals to advanced irreversible cell injury followed by necrosis in others. Activity of all enzymes studied returned or remained at control levels at 3 h. However, activities of all enzymes studied, including acid phosphatase and succinate dehydrogenase, were reduced throughout P1 and P2 at 6, 12, 24 and 48 h. By 24 and 48 h, all pars recta (P3) tubules were necrotic and enzyme activities were minimal. Administration of HgCl2 + DTT produced similar but less severe lesions at 1 h as did HgCl2-alone. However, a protective effect (morphological and enzymatic) was evident at 3 h and during the remainder of the study, when virtually no morphological or substantial enzymatic changes occurred in P1 or P2. Nevertheless, by 48 h, extensive necrosis had developed in P3 of HgCl2 + DTT treated rats as in animals treated with HgCl2-alone. DTT when administered alone produced no morphological or enzymatic abnormalities. The results of this study support the hypothesis that a structural-functional correlation exists between the progression of proximal convoluted tubular injury and the development of HgCl2-induced ARF, which is unrelated to necrosis in the pars recta. According to this hypothesis, HgCl2-induced alterations in proximal tubular handling of Na+ and Cl- lead to an augmentation of a tubulo-glomerular feedback mechanism involving the renin-angiotensin system. This results in vasoconstriction of the afferent arteriole and subsequent filtration failure. DTT ameliorates HgCl2-induced ARF by altering the effect of the heavy metal on Na+ and Cl- transport functions and the subsequent initiation of such a feedback mechanism.

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