Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022672 (acute tubular necrosis)
 2,175 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats were injected intraperitoneally with HgCl2 at doses of 2.5, 5, 7.5, and 10 mumol of Hg/kg. Urine was collected over a 24-hr period. At this time, plasma samples were taken and kidney damage was assessed by histological examination. Urinary gamma-glutamyltransferase levels were significantly elevated at Hg2+ doses of 7.5 and 10 mumol/kg, consistent with the detection of acute tubular necrosis by light microscopy. Resonances for a large number of low molecular weight metabolites were assigned in high resolution 1H NMR spectra of rat urine. Spectra from small volumes of urine (about 0.5 ml) were obtained in less than 5 min with no pretreatment. Significant Hg2+ dose-related decreases in the excretion of creatinine and citrate and increases of glucose, glycine, alanine, alpha-ketoglutarate, succinate, and acetate were detected. Elevated levels of lactate and creatinine in plasma of rats receiving the two highest doses were found by 1H NMR. There was a good correspondence between the histopathology, enzyme excretion, and 1H NMR urinary metabolite fingerprints in the assessment of Hg2+-induced renal damage. 1H NMR provided a sensitive measure of mercury-induced nephrotoxic lesions, and information on the molecular basis of mercury cytotoxicity was derived from the abnormal patterns of metabolite excretion. These suggested that primary metabolic effects of mercury were upon mitochondrial metabolism, in particular inhibition of certain citric acid cycle enzymes leading to decreased utilization of alpha-ketoglutarate and succinate by the renal tubular cells. The decrease in urinary citrate associated with Hg2+ dosing was attributed to intracellular, tubular acidosis with concomitant enhanced citrate reabsorption. The acidosis was assumed to arise from a combination of the inhibition of tubular carbonic anhydrase and a mild metabolic lactic acidosis due to increased activity of anaerobic pathways in the kidney. The possible extension of the 1H NMR techniques to the investigation of the nephrotoxic potential of other compounds and drugs is discussed.
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PMID:Proton NMR spectra of urine as indicators of renal damage. Mercury-induced nephrotoxicity in rats. 286 May 59

The mushroom metabolite gamma-L-glutaminyl-3,4-dihydroxybenzene (GDHB) was found to have an LD50 of 100 to 200 mg/kg in neonatal C57Bl/6J mice. Adult mice given 200 mg/kg GDHB showed histopathologic evidence of proximal convoluted tubular injury as early as 2 hours after injection, which progressed by 24 hours to profound acute tubular necrosis. Focal acinar epithelial cell necrosis in the pancreas was also observed. The time course and location of the injury suggested that appearance of the ultimate toxic metabolite could be due to cleavage of GDHB by gamma-glutamyl transpeptidase (GGTP). The reaction in vitro of GDHB with crude porcine GGTP resulted in the release of 4-amino-catechol which air oxidized to 2-hydroxy--4-iminoquinone (HIQ), a known sulfhydryl reagent and cytotoxic compound. Synthesis of N2-methyl-gamma-glutaminyl-3,4-dihydroxybenzene (MeGDHB) provided a compound whose oxidized derivatives, when compared with those of GDHB, had similar half-wave potentials and visible absorption maxima. MeGDHB was resistant to cleavage by GGTP and was without apparent toxicitiy at 2-3 times the LD50 of GDHB. Therefore, cleavage by GGTP, an enzymatic transformation accessible to GDHB but unavailable to MeGDHB, is proposed as the mechanism of activation of the mushroom metabolite. The following pathogenic sequence is indicated: 1) release of 4-aminocatechol from GDHB by the action of GGTP and 2) irreversible injury resulting both from the generation of free radicals by the autoxidation of 4-aminocatechol and from the reaction of HIQ with cellular nucleophils, particularly sulfhydryl groups.
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PMID:The role of gamma-glutamyl transpeptidase in the nephrotoxicity of an Agaricus bisporus metabolite. 610 87

To elucidate the renal injury induced by gold treatment, we administered various doses of gold sodium thiomalate (GST) to Wistar rats and investigated alterations in the urinary enzyme activity, gamma-glutamyl transpeptidase (gamma GTP) and N-acetyl-beta-glucosaminidase (NAG) activity, and histochemical change of enzymes, gamma GTP, alkaline phosphatase (ALP) and acid phosphatase (ACP) activity in the renal tissue. The single administration of a large dose of gold salts induced acute tubular necrosis and enzyme leakage was detected histochemically without damage to the glomerulus. After chronic administration of small doses of gold salts, the urinary gamma GTP activities gradually increased, but urinary NAG activities did not. These findings suggested that the change in urinary enzyme activities, which leaked from inside of brushborder or lysosome, indicated the degree or localization of tubular damage, because renal tubules were selectively injured by gold salts.
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PMID:Changes in urinary enzyme activity and histochemical findings in experimental tubular injury induced by gold sodium thiomalate. 886 77

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.
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PMID:[HgCl2-induced acute renal failure and its pathophysiology]. 952 59

Renal function in the early post-transplantation period depends largely on factors affecting the kidney prior to implantation. Function of the graft may be also disturbed by the most common complications of the early post-operative period such as acute graft rejection (AGR), acute tubular necrosis (ATN) and may be modified by nephrotoxic action of cyclosporine A (CsA). Evaluation of excretion of enzymes and low molecular weight proteins (LMWP) may help in the differentiation of these complications. Aim Comparison of the urinary excretion of markers of tubular injury in patients with AGR, ATN, or patients with stable graft function (SGF) was made and differences between groups and correlations between markers and cold ischemia time (CIT), warm ischemia time (WIT) and blood trough level of cyclosporine A (CsA0) were determined. Material and methods In 60 cadaveric renal allograft recipients in the early post-transplantation period urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and B isoenzyme (NAG-B), alanylaminopeptidase (AAP), gamma-glutamyltransferase (GGT), alpha and pi isoenzymes of glutathione S-transferase (alpha-GST, pi-GST), retinol binding protein (RBP) and beta2- microglobulin (beta2M), were analyzed. Results NAG and NAB-B activities were higher in ATN (P<0.05, P<0.01) and in AGR (P<0.005, P<0.02) than in SGF. Excretion of pi-GST was higher in AGR than in SGF (P<0.0002) or ATN (P<0.007). CIT and WIT in patients with ATN were higher (P<0.05) than in SGF group. In ATN patients, correlations of CIT with RBP (P<0.05) and pi-GST (P<0.05), and WIT with RBP (P<0.05), and pi-GST (P<0.001) were found. Conclusions High urinary NAG and NAG B excretion characterizes ATN and AGR patients. Evaluating urinary excretion of pi-GST may be helpful in differentiating AGR from ATN. However, taking into account ischemia time is necessary in interpreting the pi-GST value in early post transplant period.
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PMID:Enzymuria and low molecular weight protein excretion as the differentiating marker of complications in the early post kidney transplantation period. 1716 Apr 49