MLL rearrangements emerge during spontaneous apoptosis of clinical blood samples.
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Acute Disease↗
Biomedical subjects
L Trumper
Publications and source records attributed to L Trumper.
Cortical Na+,K+-ATPase activity, abundance and distribution after in vivo renal ischemia without reperfusion in rats.
The aim of our work was to study the changes in activity, abundance and distribution of sodium, potassium-adenosine triphosphatase (Na+,K+-ATPase) in membranes of cortical tubular cells in an in vivo model of ischemic injury without reperfusion. Na+,K+-ATPase, alkaline phosphatase (AP) activities and their distribution in membranes isolated from renal cortex using a Percoll gradient were studied after different ischemic periods. Na+,K+-ATPase alpha-subunit protein abundance was analysed by Western-blot. Plasma urea and cortical adenosine 5' triphosphate (ATP) were also measured. In cortical homogenates 5 min of ischemia promoted a diminution in ATP content. Na+,K+-ATPase activity diminished after 40 min and AP after 100 min of ischemia. Na+,K+-ATPase activity in the Percoll gradient fractions after 5 min peaked at a higher density and was significantly decreased after 40 min. AP activity was decreased in typically enriched apical membranes after both times of ischemia. At each time studied Na+,K+-ATPase abundance was increased in cortical homogenates and membranes. Our results showed opposite effects of ischemia on Na+,K+-ATPase activity and abundance. Increased levels of Na+,K+-ATPase protein were observed. The enzyme would be rapidly delivered to membrane domains and become inactivated as ischemia persists.
Acute Kidney Injury↗
Effect of acetaminophen on Na(+), K(+) ATPase and alkaline phosphatase on plasma membranes of renal proximal tubules.
In previous work we reported that 1 h after acetaminophen (APAP) administration, tubular function remained at control values, while 16 h later a significant deterioration of tubular function was observed. The aim of the present work was to study if APAP induces its renal toxic effects by altering the normal activity of key tubular plasma membrane enzymes. We analyzed the effects of a nephrotoxic dose of APAP (1000 mg/kg b.wt., i.p.) on the activities of the brush-border membrane (BBM) enzyme, alkaline phosphatase, and the basolateral membrane (BLM) enzyme Na(+), K(+) ATPase 1 h (APAP(1h)) and 16 h (APAP(16h)) after dosing. Na(+), K(+) ATPase abundance in homogenates and each membrane domain were analyzed by Western blot. Cortical adenosine 5' triphosphate (ATP) content was also evaluated. At each time studied, APAP promoted a diminution of alkaline phosphatase in BBM. Na(+), K(+) ATPase activity in BLM showed a biphasic response to APAP. One hour after APAP administration it was significantly increased, but it was decreased 16 h after dosing. Na(+), K(+) ATPase protein abundance was elevated in homogenates, BLM, and BBM after 1 h of APAP dosing. After 16 h, Na(+), K(+) ATPase abundance was increased in homogenates, while in BLM it was decreased. No differences were observed in cortical ATP content in each time studied. Our present results could contribute to the understanding of the molecular basis of the previously reported time course alteration in the fractional excretion of sodium promoted by a nephrotoxic dose of APAP.
Acetaminophen↗
Probenecid protects against In vivo acetaminophen-induced nephrotoxicity in male Wistar rats.
Renal effects of acetaminophen (APAP) were studied in rats pretreated with probenecid to analyze whether acute APAP-induced nephrotoxicity could be related to a probenecid-sensitive transport system for APAP or its S-derived conjugates. The administration of probenecid (200 mg/kg b.wt. i.p.) 30 min before APAP administration (1000 mg/kg b.wt. i.p.) improved urine flow rate and protected against the alterations on glomerular filtration rate and urea and creatinine plasma levels induced by APAP. Fewer epithelial cells and granular casts and a decrease in the urinary excretion of protein and glucose were observed in rats pretreated with probenecid. Probenecid pretreatment promoted an elevation in the urinary 16-hr excretion of APAP and a diminution in the plasma levels attained by APAP. These results suggest that protection afforded by probenecid in vivo could be a consequence of the inhibition of APAP S-conjugate renal uptake and/or an increase in APAP renal clearance. The effects of APAP in presence of probenecid were studied with the isolated perfused kidney model. Perfusion with probenecid (0.1 mM) before APAP (10 mM) did not change APAP direct renal effects, APAP urinary excretion, or APAP renal clearance relative to glomerular filtration rate. Our results suggest that protection afforded by probenecid in vivo could be the result of the inhibition of the uptake of nephrotoxic APAP metabolites and/or a diuresis-induced enhanced APAP renal excretion.
Acetaminophen↗
Nephrotoxicity of acetaminophen in male Wistar rats: role of hepatically derived metabolites.
The role of hepatically derived metabolites was studied in rats treated with a nephrotoxic dose of acetaminophen (APAP, 1000 mg/kg b.wt. i.p.). Hepatic glutathione (GSH) content 16 h after APAP dosing was significantly decreased (control = 3.83 +/- 0.1, APAP = 2.51 +/- 0.3 mumol/g wet tissue), whereas renal GSH levels were not changed. The role of hepatically derived GSH conjugates was investigated by administering the gamma-glutamyl-transpeptidase inhibitor, acivicin (20 mg/kg b.wt. i.p.). Treatment with acivicin led to a significant decrease in hepatic and renal gamma-glutamyltranspeptidase activity. Administration of acivicin 1 h before APAP administration protected against the alterations of glomerular filtration rate and urea and creatinine plasma levels induced by APAP. The appearance of epithelial cells and granular casts as well as the urinary excretion of protein and glucose were decreased compared with rats not pretreated with acivicin. Hepatocellular damage (evaluated by glutamic pyruvic transaminase levels) induced by APAP was not altered by acivicin pretreatment. APAP plasma levels and its urinary excretion were the same whether the rats were pretreated with acivicin or not. A group of rats was fitted with an exteriorized biliary cannula before APAP administration to study the contribution of the biliary excretion route of APAP metabolites in the APAP-induced renal damage. No differences were observed on APAP-induced renal effects between rats cannulated or not. Our results suggest that hepatically derived APAP metabolites are partially responsible for APAP renal effects. The sinusoidal efflux of these metabolites is also suggested.
Acetaminophen↗
Effects of gamma-aminobutyric acid agonists on the isolated perfused rat kidney.
The effects of gamma-aminobutyric acid (GABA) agonists were studied in the isolated perfused rat kidney. Perfusions were performed at constant flow with modified Ringer-Krebs solution. The GABAA agonist muscimol (0.1-75 microM) induced an increase in fractional excretion of water and sodium without promoting hemodynamic changes. These tubular changes were inhibited by atropine pretreatment. Thus, a possible modulation of tubular transport mechanisms via GABAA receptors acting on cholinergic system could be suggested. Muscimol was unable to modify the renal vascular resistance either at basal conditions or in noradrenaline-pretreated preparations. However, the GABAA antagonist bicuculline (50 microM) evoked an increased perfusion pressure. Despite the speculation that endogenous GABA could result in a maximal activation of these GABAergic processes, nonspecific binding sites for bicuculline should be considered. The GABAB agonist baclofen (0.05-500 microM) elicited a raised perfusion pressure and diminished glomerular filtration rate, accompanied by an increment in fractional excretion of water, sodium and glucose. These findings suggest a major GABAB receptor-mediated vasoconstriction at the afferent arteriole level. Proximal tubular structures seem to be a biological target for baclofen. GABA (0.05-1000 microM) evoked changes similar to those described for baclofen, although the glomerular filtration rate was not diminished. Data from this study indicate that the GABA system may be involved in the modulation of rat renal function.
Animals↗
Vascular and tubular actions of diazepam in isolated and perfused rat kidney.
The effects of diazepam were studied in the isolated rat kidney under conditions of constant flow. Kidneys were perfused with modified Ringer-Krebs solution. Diazepam produced a raised fractional excretion of water and sodium without hemodynamic changes, suggesting a direct effect on tubular transport mechanisms. Diazepam decreased renal perfusion pressure in a concentration-dependent fashion when kidneys were pretreated with either noradrenaline or potassium chloride. Similar responses were observed when 7-chloro-5-[4-chloro-phenyl]-1, 3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro 5-4864) or clonazepam was used. These data provide evidence for a relaxant effect of benzodiazepines on preconstricted renal vasculature.
Animals↗
Tubular effects of acetaminophen in the isolated perfused rat kidney.
The effects of different acetaminophen (APAP) concentrations (1, 5 or 10 mM) on renal function were investigated in the isolated perfused rat kidney (IPK). APAP was added to the perfusion media as a single dose after a equilibration time and control periods. Changes in fractional excretion of sodium (FENa), water (FEH2O), glucose (FEglu) and in glomerular filtration rate (GFR) were measured. The lower concentration used only modified the FEH2O. APAP 10 mM induced an increment in FEH2O (72% higher than control preparation), FENa (79% higher than control preparation) and an elevation in glucose excretion (55% higher than control preparation), associated with a decrease in GFR (23% lower than control preparation). The influence of PGE2 on the effects of APAP was also investigated. PGE2 prevented the APAP-induced decrease in GFR and in glucose reabsorption, but did not change the pattern of sodium and water handling. The effects of another vasodilator, verapamil, on APAP-induced renal effects were also tested. Verapamil prevented the glomerular but not the tubular effects of APAP. Urinary APAP excretion data showed a similar availability of APAP to the tubular cells in all the groups. Our data suggest that APAP exerts a direct action in the IPK, affecting hemodynamic and tubular functions, and that the latter are not a consequence of hemodynamic alterations.
Acetaminophen↗
Acetaminophen nephrotoxicity in male Wistar rats.
Acute acetaminophen (APAP) nephrotoxicity was studied in male Wistar rats 1 h after different APAP single doses (200, 500 and 1000 mg/kg body wt, i.p.). Significant impairments in glomerular filtration rate (GFR) and clearance of p-aminohippuric acid (ClPAH) were observed in a dose-dependent way, although tubular parameters measured, water and electrolyte fractional excretion, remained at control values, while the urine to plasma osmolality ratios (Uosm/Posm) were diminished in APAP-1000 rats (control = 2.93 +/- 0.20, APAP-1000 = 1.40 +/- 0.04). The time course of renal function was also studied in APAP-1000 mg/kg-treated animals; parallel impairments were observed in GFR, ClPAH and tubular functions. Maximal alteration was observed at 16 h and restorement began at 24 h post-injection. Glucose renal handling, either at low or at high tubular glucose loads, remained at control values. Thus, our data suggest that the early stage of acetaminophen nephrotoxicity might be due to renal hemodynamic changes which might induce an alteration in tubular function principally in distal structures of medullary tissue, as shown by the Uosm/Posm results. These effects occurred coupled with a diminution in hepatic glutathione (GSH) levels at every APAP dose and in renal GSH levels in APAP-1000 mg/kg-treated rats. Moreover, renal damage was observed both in the presence or absence of hepatic damage.
Acetaminophen↗
Estimation of bone turnover in climacteric women by the whole body retention of fluoride.
This paper reports the measurement of whole body retention using fluoride (WBRF) as an estimator of skeletal turnover in a group of climacteric women that received an oral dose of 700 mumol of sodium fluoride. WBRF is defined as 100(1-(urinary fluoride/fluoride load)). WBRF was significantly correlated with whole body retention of 99m-Tc-methylene-diphosphonate, the serum levels of the bone alkaline phosphatase and the urinary excretion of hydroxyproline. WBRF values ranged from 20% to 95% and were affected by calcium intake and the urinary calcium excretion. In normal subjects with high turnover, the measurement of serum alkaline phosphatase activity and/or urinary hydroxyproline excretion helps to distinguish these cases from patients with metabolic bone diseases due to metastases, Paget disease, etc. The fact that the fraction of fluoride not incorporated into bone is not further metabolized plus the accuracy, preciseness and rapidity of fluoride measurements in urine are the main advantages of this technique.
Alkaline Phosphatase↗
Nephroblastoma with neuroendocrine differentiation.
A nephroblastoma (Wilms' tumor) with morphological, histochemical, immunohistochemical and ultrastructural evidence of neuroendocrine differentiation is described. Whereas areas of neural differentiation and occasional argyrophilic cells in cases of Wilms' tumor have been previously reported, the unique characteristic in this case was the extent of the neuroendocrine differentiation, as shown by a strong Grimelius stain of over 90% of the blastematous cells. Immunoperoxidase studies employing antibodies to neuron-specific enolase and ultrastructural data were also in favor of the neuroendocrine differentiation and suggested the existence, in addition to the already reported variant of Wilms' tumor with neural differentiation, of a neuroendocrine variant which may be part of the histologic spectrum of this neoplasm.
Cell Differentiation↗