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  • 1
    Electronic Resource
    Electronic Resource
    Selective cytotoxicity associated with in vitro exposure of fresh rat renal fragments and continuous cell lines to atractyloside (1996)
    Springer
    Archives of toxicology 71 (1996), S. 93-98 
    Details
    ISSN: 1432-0738
    Keywords: Key words Atractyloside ; Renal marker enzymes ; Continuous renal cell lines ; Proximal tubular fragments ; Glomeruli
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The consumption of plants containing the diterpenoid atractyloside (ATR) causes selective proximal tubule injury, renal failure and death in humans. We have compared the effects of ATR in freshly isolated renal proximal tubules and glomeruli from rat and also in cell lines: NRK, derived from the proximal tubules, and MDBK and MDCK more closely representing the distal nephron. The effects of ATR (10– 500 μM) on proximal tubules and glomeruli were assessed by changes in lipid peroxidation, de novo protein synthesis and the leakage of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH) and N-acetyl-β-D-glucosaminidase (NAG). The susceptibility of NRK, MDBK and MDCK cell lines to ATR was assessed by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, measuring mitochondrial reduction. Enzyme leakage was the most sensitive of the markers of cell injury in fresh fragments and ranked LDH〉GDH〉ALP〉NAG in proximal tubules. As little as 20 μM ATR caused significant enzyme leakage from proximal tubules, but there were no increases in enzyme leakage from glomeruli at concentrations ?500 μM ATR. De novo protein synthesis was only inhibited 50% at ATR concentration 〉5 mM in the proximal tubules, but there were no effects in glomeruli. Malondialdehyde production was significantly elevated at 1 mM ATR for proximal tubules, and 500 μM for glomeruli. NRK cells were sensitive to ATR (IC50, 120 μM), but MDBK or MDCK cells were unaffected by?1 mM of this diterpenoid. Both freshly isolated fragments and continuous cell lines representing the proximal tubules are more sensitive to ATR than either glomeruli or cells representing the distal nephron. These data also show that protein synthesis is a less specific and sensitive measure of ATR cytotoxicity than enzyme leakage in fragments. MTT reduction to formazan was the most sensitive in the NRK cell line. The low levels of lipid peroxidation products in proximal tubular fragments or sensitive renal cell lines at toxic levels of ATR suggest that oxidative injury is not a key mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050362
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    The toxic mechanism and metabolic effects of atractyloside in precision-cut pig kidney and liver slices (1998)
    Springer
    Archives of toxicology 72 (1998), S. 524-530 
    Details
    ISSN: 1432-0738
    Keywords: Key words Atractyloside ; Pig kidney and liver slices ; Metabolic alterations ; Energy status ; Selective toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The toxic and cellular metabolic effects of atractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and humans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 μm thick) were incubated with atractyloside at concentrations of 200 μM, 500 μ M, 1.0 mM and 2.0 mM for 3 h at 37 °C and changes in lipid profile and pyruvate-stimulated gluconeogenesis investigated. Lipid peroxidative changes, reduced glutathione (GSH) and ATP content, the release of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine and aspartate aminotransferase (ALT/AST) were also assessed. After 3 h of incubation, atractyloside caused a significant (P 〈 0.01) and concentration-dependent leakage of LDH and ALP from kidney slices. Only LDH leakage was significantly elevated in liver slices while ALT and AST leakage showed marginal increase. Atractyloside at concentrations of ≥200 μ M caused a significant increase in lipid peroxidation, but only in liver slices. However, atractyloside at concentrations of ≥200 μ M caused a marked depletion of GSH and ATP content in both kidney and liver slices. There was a marked decrease in total and individual phospholipid in kidney but not in liver slices. However, cholesterol and triacylglycerol levels were not affected by atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P 〈 0.05) inhibited at atractyloside concentrations of ≥500 μM. Accumulation of organic anion p-aminohippuric acid (PAH) was also inhibited in renal cortical slices at atractyloside concentrations of ≥500 μM. These results suggest that the observable in vivo effect of atractyloside can be reproduced in slices and that basic mechanistic differences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possibility that the mechanistic basis of metabolic alterations in these tissues following treatment with atractyloside may be relevant to target selective toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050537
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Changes in urinary enzyme levels following the use of antihypertensive agents in patients with essential hypertension (1995)
    Springer
    Cardiovascular drugs and therapy 9 (1995), S. 407-412 
    Details
    ISSN: 1573-7241
    Keywords: Brinerdin ; Minizide ; antihypertensive agents ; enzymuria ; proteinuria ; renal damage ; essential hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary When choosing antihypertensive agents for the treatment of hypertension, it is necessary to consider the predisposition of individuals to renal damage, which may be associated with the long-term effect of such agents. In this respect, this study examined the effect of two commonly used antihypertensive drugs (Brinerdin and Minizide) on renal function over 24 months in patients diagnosed as having essential hypertension. We utilized urinary enzyme studies, which are indicators of subtle renal dysfunction. Other parameters of glomerular and tubular function were also determined in the pretreatment period, as well as during and at the end of treatment of 28 patients (16 males and 12 females) with therapeutic doses of Brinerdin and 22 patients (12 males and 10 females) with conventional doses of Minizide. During the follow-up period, blood pressure (BP) fell from a mean of 160/108±9/4 (SD) mmHg to 130/90±7/4 on Brinerdin and from a mean of 160/106±5/2 (SD) mmHg to 130/90±8/5 on Minizide. There was no significant difference in the levels of BP between the patients taking Minizide and those taking Brinerdin before, during, and at the end of treatment. Significant elevation (p〈0.05) of the levels of urinary protein, lactate dehydrogenase (LDH), and N-acetyl-B-D-glycosaminidase (NAG) was observed in patients on Minizide during treatment, and these levels remained elevated during the latter part of the study. Normotensive, untreated, age-and sex-matched control subjects showed no such urinary parameter changes. While NAG activity was significantly elevated in the Brinerdin-treated patients, other parameters remained within comparable levels to those of normotensive, untreated control subjects throughout the period of study. However, a significant reduction in the serum potassium level (−0.58±0.06 mmol/l) was observed following Minizide therapy compared with a mild reduction (−0.25±0.05 mmol/l) following Brinerdin treatment. Female and male patients exhibited similar patterns of response to the two drugs. The results of the present study suggest that transient but subtle tubular injury has been induced by the use of the two drugs with a more profound effect from the use of Minizide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00879029
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    Paper (German National Licenses)
    Fulltext
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