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Glutamine synthetase activity in rat urine as sensitive marker to detect S3 segment-speciflc injury of proximal tubule induced by xenobiotics.
Full text linkThe possibility of detecting segment-specific injury of the proximal tubule by means of urinary enzymes was investigated in rats. Urinary glutamine synthetase, an enzyme exclusively localized in the S3 segment, and N-acetyl-beta-D-glucosaminidase, prevalently a S1-S2, but S3 enzyme also, were determined after single treatment with 100 mg/kg body wt. of hexachloro-1:3-butadiene (HCBD; i.p.), toxic for the S3 segment, or 25 mg/kg body wt. of potassium dichromate (s.c.), toxic for the S1-S2 segments. Excretion of total urinary proteins was also measured. In addition, a dose-response relationship was determined between three doses (50, 100 and 200 mg/kg body wt.) of HCBD and glutamine synthetase activity in urine. Glutamine synthetase activity, measured according to a new assay for urine based on modification of methods developed for organs, increased in the urine only when the S3 segment of the proximal tubule was damaged, as demonstrated by histological findings of the kidneys. HCBD caused early excretion of the enzyme related to the necrosis of the S3 segment, whereas potassium dichromate caused a slight increase only when the resulting lesion to this segment (vacuolization) began to develop. On the contrary, N-acetyl-beta-D-glucosaminidase activity showed the peak of excretion 24 and 34 h after treatment with HCBD or potassium dichromate, respectively, according to the histological findings of necrosis of the S3 segment (the former) and vacuolization of the S1-S2 segments (the latter). Excretion of total urinary proteins reached the peak 24 h (HCBD) and 48 h (potassium dichromate) after treatment. HCBD at 200 mg/kg body wt, caused a peak of glutamine synthetase activity in urine 10 h after injection, whereas the peak caused by doses of 50 and 100 mg/kg body wt. occurred 24 h following treatment. The peak of enzyme activity in urine significantly increased with the dose. The results suggest that the measurement of urinary activity of S3 segment-specific enzyme as glutamine synthetase allows us to detect early S3 segment-specific injury of the proximal tubule. In addition, the method for urinary enzyme activity appears sensitive, simple and fast
Three common pathways of nephrotoxicity induced by halogenated alkenes.
No full textGlutathione-dependent bioactivation is a common pathway in nephrotoxicity caused by haloalkanes and haloalkenes. Glutathione-conjugation forms the link between halogenated hydrocarbons, based on the formation of an episulfonium ion (vicinal halomethanes) or a cysteine conjugate (haloalkenes). Herein we review the metabolic pathways underlying the nephrotoxic effects of the three well known haloalkenes trichloroethylene, tetrachloroethylene, and hexachloro-1:3-butadiene to emphasize the role of cysteine-conjugate β-lyase and the oxidative metabolism in renal toxicity. Activation by cysteine-conjugate β-lyase is the best-characterized mechanism causing toxicity due to haloalkene treatment in experimental models. However, the severity of toxicity differs considerably, with S-(1,2,2-trichlorovinyl)-L-cysteine being more toxic than S-(1,2-dichlorovinyl)-L-cysteine, which is in turn more toxic than S-(1,2,3,4,4-pentachloro-1:3-butadienyl)-L-cysteine. Moreover, two oxidative pathways involving cysteine S-conjugates (mediated by flavin-containing monooxigenase 3) and N-acetyl-L-cysteine conjugates (mediated by cytochrome P-450 3A) form derived sulfoxides, which represent alternative metabolites with toxic effects. In vitro and in vivo studies showed that sulfoxide metabolites are more toxic than cysteine-conjugate derivates. The cytochrome P-450 3A family on the other hand is sex-specific and its expression has only been reported in adult male rats and rabbits. In summary, haloalkenes are highly nephrotoxic in vivo and in vitro and their toxicity mechanisms are well-documented experimentally. However, little information is available on their toxicity in humans, except for the carcinogenic effects established for high exposure levels of trichloroethylene and tetrachloroethylene
Kirby diagrams and 5-colored graphs representing compact 4-manifolds
Full text linkIt is well-known that in dimension 4 any framed link (L, c) uniquely represents the PL 4-manifold M^4 (L, c) obtained from D^4 by adding 2-handles along (L, c). Moreover, if trivial dotted components are also allowed (i.e. in case of a Kirby diagram (L^(*), d)), the associated PL 4-manifold M^4(L^(*), d) is obtained from D^4 by adding 1-handles along the dotted components and 2-handles along the framed components. In this paper we study the relationships between framed links and/or Kirby diagrams and the representation theory of compact PL manifolds by edge-colored graphs: in particular, we describe how to construct algorithmically a (regular) 5-colored graph representing M^4(L^(*), d), directly "drawn over" a planar diagram of (L^(*), d), or equivalently how to algorithmically obtain a triangulation of M^4(L^(*),d). As a consequence, the procedure yields triangulations for any closed (simply-connected) PL 4-manifold admitting handle decompositions without 3-handles. Furthermore, upper bounds for both the invariants gem-complexity and regular genus of M^4(L^(*), d) are obtained, in terms of the combinatorial properties of the Kirby diagram
Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants.
Full text linkGlutamine transaminase K(GTK) excretion assessed in urine and by kidney histology was evaluated in rats after single treatment with 1.0 mg/kg i.p. of mercuric chloride, 100 mg/kg i.p. of hexachloro-1:3-butadiene (both S3, pars recta, segment-specific nephrotoxicants) and 25 mg/kg s.c. of potassium dichromate (S1-S2, pars convoluta, segment-specific nephrotoxicant). The aim was to correlate segment-specific injury and enzyme excretion in order to assess, using non-vasive methods, localization of GTK along the proximal tubule. Mercuric chloride and hexachloro-1:3-butadiene produced early focal damage in the pars recta (focal necrosis was shown 10 h after treatment, and diffuse necrosis appeared later at 34 and 24 h after treatment). Changes of the pars convoluta were occasional and delayed (72 h after treatment for both substances). On the contrary, potassium dichromate induced damage of the pars convoluta (vacuolar degeneration and focal necrosis were evident 24 h and 48 h after treatment, respectively), whereas the pars recta was affected later (focal vacuolar degeneration was observed 72 h after treatment). Increase urinary GTK excretion was early after treatment with mercuric chloride and hexachloro-1:3-butadiene (significant increase was observed within 10 h), with a peak for both substances 24 h after treatment, in agreement with the necrosis of the pars recta. Potassium dichromate induced a significant increase of enzyme excretion in urine also 24 h after injection, according to histological features showing vacuolar degeneration of the pars convoluta; the peak of excretion was reached 48 h after treatment (delay was due, probably, to s.c. administration). The results show that GTK increased in urine after treatment with S3 and S1-S2 specific nephrotoxicants; the combination of histological examination and urinary enzyme supports the evidence that the enzyme is distributed along the whole of the proximal tubule
Glutamine synthetase (GS) activity in urine as index of segment-specific injury
No full textGS, a mitochondrial enzyme present in a variety of tissues including kidney, is responsible for the production of glutamine from glutamate. In the kidney, it is localized only in the early and late portion of the pars recta of the proximal tubule. This exclusive localization may be used to study, without invasive and difficult to achieve methods, the effects of nephrotoxicants on the straight portion of the proximal tubule. Male, two months old, Wistar rats were treated with 1.0 mg/kg b.w. i.p. of mercuric chloride (Hg2+) or 100 mg/kg b.w. i.p. of hexachloro-1:3-butadiene (HCBD), both chemical specific toxicants for the straight portion, or 25 mg/kg b.w. s.c. of potassium dichromate (Cr6+), specific toxicant for the convoluted portion. Urines were collected 14 hours before and every 10 or 14 hours until 96 hours after treatment. At the same time of urine collection, histological examination of the kidney of an ancillary group treated with the same doses was performed. The results show a peak of GS excretion 24 hours after treatment with Hg2+ or HCBD, related to focal (Hg2+) or diffuse (HCBD) necrosis of the pars recta. After the peak of excretion, enzyme activity in urine decreases progressively until the end of the observation period, but it doesn’t normalize, though regeneration of the cell of the pars recta was almost complete after 96 hours for both chemicals. On the contrary, treatment with Cr6+ doesn’t affect GS excretion in urine until 72 hours after treatment, when a slight excretion of the enzyme is related to the histological findings of a focal vacuolization of the pars recta. High excretion of the enzyme appears related to the necrosis of the straight segment, because damage without necrosis, as induced by Cr6+, causes only a slight excretion. This fact may be explained by the mitochondrial localization, organelles highly sensitive to the necrosis. In conclusion, specific injury of the proximal straight tubule may be well defined by means of urinary GS. In our opinion, segment-specific injury by nephrotoxicants may be measured by means of tubular enzymes. In addition, segment-specific origin may be defined by means of segment-specific nephrotoxicants
Sex-related differences in renal toxicodynamics in rodents
Full text linkIntroduction: An issue yet to be addressed, in the investigation of the xenobiotic toxicity, is a detailed characterization of the sex differences in toxicological responses. The ‘sex issue’ is significant in nephrotoxicology as the kidney is a relevant target organ for xenobiotics and few studies have approached this subject in the past. There is a strong need to improve our understanding regarding the influence of sex in toxicology, given their increased requirement to establish the limits of exposure to chemicals in the environment and at work. Areas covered: In this review, the authors provide the reader with the current knowledge of sex differences in kidney toxicity for rats and mice. To make the review easier to consult, these studies have been organized according to the class of xenobiotic. Expert opinion: From the analysis of the present knowledge emerges a dramatic need for information on sex differences in xenobiotics toxicity. Although animals are reasonably good predictors of adverse renal effects in patients, there is need to identify alternative methods (e.g. in vitro/ex vivo) to better study sex differences in organ toxicity
Renal proximal tubule segment-specific nephrotoxicity: An overview on biomarkers and histopathology
No full textThe correspondence between histopathological findings and segment-specific biomarkers was investigated in rats treated with segment-specific nephrotoxicants. Male Wistar rats were treated with a single injection of K2Cr2O7 (25 mg/kg sc in saline), cis-Pt (10 mg/kg ip in buffered MSO) or HCBD (100 mg/kg ip in corn oil). Twenty-four and 48 hours after treatment, the rats were sacrificed and the kidneys were drawn for histopathological and biochemical evaluation, i.e., GS activity in renal cortex and PAH uptake in renal cortical slices. Histopathological findings show that cis-Pt and HCBD cause diffuse necrosis of S-3 segment of proximal tubules in the outer stripe of outer medulla, respectively. On the contrary, K2Cr2O7 damages exclusively S-1-S-2 segments, inducing vacuolization at 24 hr and diffuse necrosis at 48 hr after treatment. GS activity in renal tissue is significantly decreased after HCBD and cis-Pt, but not K2Cr2O7 treatment. In contrast, PAH uptake is significantly reduced by K2Cr2O7, but not by cis-Pt or HCBD treatment (even if HCBD causes a slight decrease 48 hr after treatment). The evidence of this study confirms the high specificity of GS activity as marker of S-3 segment injury, that PAH uptake is prevalently active in the S-1-S-2 Segments, and that there is complete correspondence among segment-specific nephrotoxicants, biomarkers of segment-specific damage, and histopathological findings
Anti-atherosclerotic activity of the calcium antagonist lacidipine in cholesterol-fed hamsters
No full textWe have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins: these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 ± 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells: lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity. (C) 2000 Editions scientifiques et medicales Elsevier SAS
Qualitative and quantitative analysis of the progressive cerebral damage after middle cerebral artery occlusion in mice.
No full textGem-induced trisections of compact PL -manifolds
Full text linkThe idea of studying trisections of closed smooth -manifolds via
(singular) triangulations, endowed with a suitable vertex-labelling by three
colors, is due to Bell, Hass, Rubinstein and Tillmann, and has been applied by
Spreer and Tillmann to colored triangulations associated to the so called
simple crystallizations of standard simply-connected -manifolds. The present
paper performs a generalization of these ideas along two different directions:
first, we take in consideration also compact PL -manifolds with connected
boundary, introducing a possible extension of trisections to the boundary case;
then, we analyze the trisections induced not only by simple crystallizations,
but by any 5-colored graph encoding a simply-connected -manifold. This
extended notion is referred to as gem-induced trisection, and gives rise to the
G-trisection genus, generalizing the well-known trisection genus. Both in the
closed and boundary case, we give conditions on a 5-colored graph which ensure
one of its gem-induced trisections - if any - to realize the G-trisection
genus, and prove how to determine it directly from the graph itself. Moreover,
the existence of gem-induced trisections and an estimation of the G-trisection
genus via surgery description is obtained, for each compact simply-connected PL
4-manifold admitting a handle decomposition lacking in 1-handles and 3-handles.
As a consequence, we prove that the G-trisection genus equals for all
-bundles of , and hence it is not finite-to-one.Comment: 24 pages, 14 figures. Several changes were made to the structure of
the paper; in particular, Section 4 generalizes old Section 3 including Kirby
diagrams with dotted components, to
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