| Abstrakt: |
Studies were undertaken to investigate the effect of dithiothreitol (DTT), an agent capable of chelating heavy metals, on mercuric chloride (HgCl)-induced acute renal failure (ARF) in rats. The rats were divided into four groups: Control; HgCl (4 mg/kg)-alone; DTT (15.4 mg/kg)-alone; and HgCl followed 30 min later by DTT (HgCl + 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, HgCl-alone induced a progressive non-oliguric form of ARF characterized by increased fractional excretion of sodium (FE+), a reduction in glomerular filtration rate (GFR) and azotemia, apparent by 12 h and continuing throughout the course of study. Administration of HgCl + DTT ameliorated the development of ARF whereas DTT, administered by itself, produced no functional abnormality. Administration of HgCl-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 (P) tended to be reversible. The injury which occurred in the more terminal portions of the pars convoluta (P) 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 P and P at 6, 12, 24 and 48 h. By 24 and 48 h, all pars recta (P) tubules were necrotic and enzyme activities were minimal. Administration of HgCl + DTT produced similar but less severe lesions at 1 h as did HgCl-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 P or P. Nevertheless, by 48 h, extensive necrosis had developed in P of HgCl + DTT treated rats as in animals treated with HgCl-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 HgCl-induced ARF, which is unrelated to necrosis in the pars recta. According to this hypothesis, HgCl-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 HgCl-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. [ABSTRACT FROM AUTHOR] |
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