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)

The present study was designed to determine whether the administration of free radical scavengers, superoxide dismutase (SOD), catalase or dimethylsulfoxide (DMSO) is able to ameliorate ischemia/reperfusion injury in the canine kidney and also ascertain whether or not a relationship exists between oxygen free radicals and membrane-bound Na(+)-K(+)-ATPase activity. In 23 dogs, the vascular pedicle of the left kidney was clamped for 75 min at room temperature. The experimental animals received free radical scavengers for 30 min starting at 2 min prior to reperfusion. Renal tissue specimens were enzyme-histochemically examined regarding the activity of membrane-bound Na(+)-K(+)-ATPase, and a marked reduction just before reperfusion was revealed. The SOD- and the DMSO-treated groups showed a marked recovery of the membrane-bound Na(+)-K(+)-ATPase activity; however, the untreated and the catalase-treated groups still demonstrated a marked reduction 1 day after reperfusion. At the same time, widespread acute tubular necrosis in the cortex was observed in the untreated and catalase groups in comparison with the SOD and the DMSO groups. In addition, the SOD and the DMSO groups significantly preserved better renal function. Based on these findings, it was thus concluded that free radical scavengers ameliorate the recovery of depressed membrane-bound Na(+)-K(+)-ATPase activity and ischemia/reperfusion injury in the canine kidney.
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PMID:The influence of oxygen free radical scavengers on the reduction of membrane-bound Na(+)-K(+)-ATPase activity induced by ischemia/reperfusion injury in the canine kidney. 873 Apr 34

Acephate (AT) is an organophosphate (OP) insecticide. Due to their reputation for low environmental persistence, OP pesticides are often used indiscriminately resulting in detrimental exposure to humans and other nontarget species. Although the toxicity of OP compounds is primarily through blockade of neural transmission via inhibition of acetylcholinesterase, studies have revealed histopathological alterations in the renal proximal tubules, suggesting a role for additional mechanisms in renal toxicity. It is our hypothesis that Reactive Oxygen Species (ROS) may play a role in OP-induced renal tubular injury for the following reasoning. Renal tubular cells concentrate many nephrotoxic chemicals including OPs, and renal injury from many of these compounds has been shown to arise from excessive ROS production. Furthermore, it has been established that many phosphorothiolates, which are sulfur-containing OPs and constitute the class of OP compounds to which AT belongs, are S-oxidized to highly reactive intermediates within cells and tissues. Because of these considerations, we examined whether ROS play a role in OP-induced renal tubular epithelial cell (LLC-PK1) toxicity using AT as a prototype. AT produced a concentration- and time-dependent increase in cell damage in LLC-PK1 cells, measured by lactate dehydrogenase (LDH, % of total) leakage. The cytotoxicity (LDH) induced by 2500 ppm of AT over 72 h was significantly suppressed by antioxidants 2-methylaminochroman (2-MAC) and desferrioxamine (DFO). H2O2 levels were significantly elevated following exposure of LLC-PK1 cells to 2500 ppm of AT. Malondialdehyde (MDA) formation was also significantly increased in AT-exposed cells compared to the control cells, indicating the occurrence of enhanced lipid peroxidation. 2-MAC and DFO, in addition to providing cytoprotection, inhibited AT-induced MDA generation in a significant and concentration-dependent manner. Results from this study, which is the first to explore the toxic effects of AT on renal tubular cells, demonstrate that toxic action of AT on kidney cells is partly through an ROS-mediated mechanism. Based on these direct in vitro findings, we further hypothesize that oxidant stress may play a role in the pathogenesis of AT-induced acute tubular necrosis and renal dysfunction observed in cases of AT overdoses.
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PMID:Role of oxidant stress and antioxidant protection in acephate-induced renal tubular cytotoxicity. 1004 44

Due to low toxicity to nontarget species and rapid degradation after its application, organophosphate (OP) remains a widely used class of pesticide. Suicidal or accidental overdose of OP can result in acute tubular necrosis. Experimental evidence shows little correlation between the renal tubular necrosis and the degree of OP-induced acetylcholinesterase inhibition, the main mechanism of OP's toxicity, suggesting the involvement of alternate mechanisms. Since reactive oxygen species (ROS) are known mediators of many toxin-induced renal injuries, this study was conducted to investigate whether ROS play a role in Bidrin (BD)-induced renal tubular epithelial cell (LLC-PK1) toxicity. BD is an OP insecticide formulation with dicrotophos as the active ingredient. LLC-PK1 cell death, determined by lactate dehydrogenase (LDH) release (% of total), rose concentration- and time-dependently after exposure of the cells to 1000, 1250, 1500, 1750, and 2000 ppm of BD for 6, 12, 24, and 48 h. Antioxidants 2-methylaminochroman (2-MAC; 0.3 to 2.5 microM) and desferrioxamine (DFO; 0.25 to 2 mM) reduced cell damage induced by 1250 ppm of BD over a 24-h incubation in a concentration-related manner. The greatest reductions in % LDH were produced by DFO 2 mM and 2-MAC 2.5 microM, both significantly lower than BD alone. H2O2 levels (micromol/mg protein per h) were significantly elevated after exposure to 1250 ppm of BD. Significantly increased malondialdehyde formation (nmol/mg protein) compared with control was also found in BD-exposed cells indicating enhanced lipid peroxidation. Malondialdehyde generation was significantly suppressed by 2-MAC and DFO. These results demonstrate that the organophosphate BD can cause direct tubular cytotoxicity, and implicate, at least in part, a role for ROS and accompanying lipid peroxidation in cytotoxicity. Based on these direct in vitro findings, it is hypothesized that, besides hypotension that often accompanies OP intoxication, OP-induced oxidative stress at the tubular level may play a role in the pathogenesis of acute tubular necrosis.
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PMID:Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity. 1044 42

Acute renal failure (ARF) is characterized by an acute decrease in glomerular filtration rate (GFR). ARF complicates 4% to 23% of intensive care unit admissions, and is associated with a mortality of approximately 50% among critically ill patients. In the intensive care setting the term ARF is usually applied to acute tubular necrosis (ATN), a form of intrinsic ARF caused by ischemia or nephrotoxins. Pathophysiological mechanisms involved in the decline in GFR include tubular obstruction caused by detachment of tubular epithelial cells from the basement membrane and back-leak of glomerular filtrate as a consequence of disruption of the epithelial cell layer. Vascular mechanisms involved in the pathophysiology of ATN are vasoconstriction due to an imbalance between vasoconstrictive and vasodilatory mediators and vascular obstruction caused by cell aggregation. Currently, there is no real time method to monitor renal function comparable to the real time monitoring of blood pressure or arterial oxygen saturation. Urinary output does not reflect glomerular filtration which may be critically reduced despite normal urine volumes and creatinine clearance still provides the clinically most applicable estimate of GFR. Tubular function can be assessed using the fractional excretion of sodium or the ratio of urinary and serum osmolality; both parameters can be obtained from spot samples of urine and serum and no urinary sampling period is necessary. However, both parameters are strongly affected by the administration of loop diuretics and high fluid and sodium inputs which are common in the intensive care unit. We determined the day to day variability of creatinine clearance, fractional excretion of sodium and the urinary to serum osmolality ratio in critically ill patients without renal dysfunction (i.e. creatinine clearance in the normal range) and found differences of 16% for creatinine clearance, 79% for fractional excretion of sodium and 22% for urinary to serum osmolality ratio. Treatment of ARF is mainly supportive and there is no clinically accepted therapy that attenuates the course of ATN. Treatment of the underlying disease and renal replacement therapy are the main options for the treatment of patients with ARF. In critically ill patients continuous venovenous hemo(dia)filtration is the first choice because it provides more hemodynamic and metabolic stability than intermittent therapy. Acute life-threatening hyperkalemia is an indication for intermittent hemodialysis because of the higher efficacy of dialysis in the clearance of low molecular weight substances.
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PMID:[Acute kidney failure. Physiopathology--clinical diagnosis--therapy]. 1084 May 48

We describe a case of exercise-induced acute renal failure (ARF) in a patient with hypouricemia. Following recovery from ARF, the patient's serum urate concentration was 0.6-0.9 mg/dl, and the ratio of urate clearance to creatinine clearance (Cua/Ccr) was 41.9%-56.6%. There was no change in the Cua/Ccr following the administration of pyrazinamide or probenecid, suggesting defects of tubular urate/anion exchangers. Because the renal biopsy revealed acute tubular necrosis without uric acid crystals, the ARF of this patient might be due to oxygen free radicals resulting from exercise stress and hypouricemia.
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PMID:Exercise-induced acute renal failure in a patient with renal hypouricemia. 1095 43

Acute renal failure is commonly due to acute tubular necrosis (ATN), the latter representing an acute, usually reversible loss of renal function incurred from ischemic or nephrotoxic insults occurring singly or in combination. Such insults instigate a number of processes-hemodynamic alterations, aberrant vascular responses, sublethal and lethal cell damage, inflammatory responses, and nephron obstruction-that initiate and maintain ATN. Eventually, reparative and regenerative processes facilitate the resolution of renal injury and the recovery of renal function. Focusing mainly on ischemic ATN, this article reviews evidence indicating that the inordinate or aberrant generation of reactive oxygen species (ROS) may contribute to the initiation and maintenance of ATN. This review also discusses the possibility that ROS may instigate adaptive as well as maladaptive responses in the kidney with ATN, and raises the possibility that ROS may participate in the recovery phase of ATN.
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PMID:Reactive oxygen species and acute renal failure. 1109 87

Severe muscular injury sometimes causes renal failure, and myoglobin in skeletal muscle is known to induce toxic free oxygen radicals in the kidneys. The relationship between the immunohistochemical expression of myoglobin and the scavenger copper/zinc superoxide dismutase (Cu/Zn-SOD) was investigated in kidneys taken from two autopsy groups, a group with tourniquet shock (n = 4), and a group with severely injured skeletal muscle (n = 18). Paraffin-embedded kidney sections were used for immunohistochemical staining by the avidin-biotin-complex (ABC) method using antibodies against myoglobin and Cu/Zn-SOD. Detection of the two antigens was analyzed qualitatively. In most cases of tourniquet shock in which the survival time was considered to be relatively long, myoglobin staining was positive and Cu/Zn-SOD was negative. Among the seven cases of severely injured skeletal muscle in which the survival period was considered to be relatively short, positive staining was detected immunohistochemically for both myoglobin and Cu/Zn-SOD. Moreover, in most of the cases in this group that showed acute tubular necrosis, immunohistochemical staining was negative for both markers, whereas positive staining was found for most of the cases in which the kidneys were revealed to be normal by HE staining. These findings suggest that when myoglobin enters the kidneys via the circulation, Cu/Zn-SOD reacts to eliminate free radicals, but is depleted by consumption in the long run, and that there might be a relationship between these histological findings and immunohistochemical expression.
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PMID:Immunohistochemical study of the kidneys after severe muscular injury. 1135 1

The complex pathogenesis of ischemia reperfusion injury (IRI) includes endothelial expression of adhesion molecules, leukocyte recruitment and activation, reactive oxygen species production, and apoptotic and necrotic cell death. A role for complement in IRI of different organs, including kidney, has been proposed on the basis of results of experiments that used pharmacologic inhibitors as well as animals that were deficient in individual complement proteins. Here, renal IRI in mice was examined. Animals that were deficient in C3 had partial protection from IRI induced by 27.5 min of bilateral renal ischemia, followed by 20 h of reperfusion (blood urea nitrogen [BUN] values, 46.6 +/- 6.9 and 68.4 +/- 7.9 mg/dl in C3 -/- and C3 +/+ mice; n = 7 and 8, respectively; P = 0.033). Given the reduction in IRI in C3 -/- mice, it was investigated, by use of the rodent C3 convertase inhibitor CR1-related gene/protein y-Ig (Crry-Ig), whether exogenous administration of a complement inhibitor could lessen renal injury. Despite the use of Crry-Ig in high doses, there was no significant reduction of injury induced by 20 to 30 min of ischemia followed by up to 30 h of reperfusion. Histologic examination revealed acute tubular necrosis and neutrophilic infiltration, both of which correlated significantly with BUN values (P < 0.001). Of interest, C3 deposition around renal tubules was significantly less in animals with IRI, compared with that in unmanipulated controls (P < 0.001). In Crry-Ig-treated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI allowed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in mice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of the presence of other mediator systems that operate in parallel.
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PMID:Inhibiting the complement system does not reduce injury in renal ischemia reperfusion. 1142 67

It was reported that reactive oxygen metabolites play an important role in the pathogenesis of several renal diseases including glomerulonephritis, ischemia and acute tubular necrosis. However, the effect of oxidants and protective effect of sex steroid hormones on Na+/glucose cotransporter of renal proximal tubular cells is not yet elucidated. In the present study, we examined the effect of sex steroid hormones against tert-butyl hydroperoxide (t-BHP)-induced alteration of Na+/glucose cotransporter activity in primary cultured rabbit renal proximal tubule cells (PTCs). t-BHP inhibited alpha-methyl-D-glucopyranoside (alpha-MG) uptake in a dose-dependent manner. t-BHP-induced inhibition of alpha-MG uptake was due not to Km but to the decrease of Vmax. 0.5 mM t-BHP-induced inhibition of alpha-MG uptake was significantly blocked by estradiol-17beta, but not by progesterone and testosterone. This protective effect was not blocked by estrogen receptor antagonist or transcription and translation inhibitor. In addition, 0.5 mM t-BHP increased [3H]-arachidonic acid (AA) release and Ca2+ uptake. These effects of t-BHP were also significantly blocked by estradiol-17beta, but not by progesterone and testosterone. Protective efficacy of estradiol-17beta on t-BHP-induced inhibition of alpha-MG uptake is exhibited between antioxidants and iron chelators. In conclusion, estradiol-17beta, but not progesterone and testosterone, partially prevented t-BHP-induced inhibition of alpha-MG uptake through its antioxidant activity dependent upon phenol structures and inhibition of AA release and Ca2+ influx.
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PMID:Effects of sex hormones on Na+/glucose cotransporter of renal proximal tubular cells following oxidant injury. 1152 8

Cisplatin [cis-diaminedichloroplatinum(II), CDDP] is a widely used antineoplastic drug. However, it has major side-effects such as acute tubular necrosis (ATN). There are a number of studies concerning the role of reactive oxygen radical species in the pathophysiology of CDDP-dependent ATN. Several antioxidant agents have been reported to prevent this side-effect but there is no study regarding the protective action of either physiological or pharmacological concentrations of melatonin. Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. We investigated the effects of melatonin on CDDP-induced changes of renal malondialdehyde (MDA), a lipid peroxidation product, and blood urea nitrogen (BUN) and serum creatine (Cr). The morphological changes in kidney were also examined using light microscopy. The rats were divided into two groups: pinealectomized (Px) and sham-operated (non-Px). Both CDDP and melatonin were administered to all groups. MDA levels were found to be higher in Px than non-Px animals. CDDP administration to Px or non-Px rats increased renal MDA levels and melatonin administration either before or after CDDP injection caused significant decreases in MDA in kidney compared with those in rats treated with CDDP alone. Serum levels of BUN and Cr did not change as a result of any treatment. Morphological tubule damage because of CDDP was more severe in the renal cortex than in the medulla. The damage to the kidney induced by CDDP was reversed by melatonin. The results show that pharmacological and physiological concentrations of melatonin reduce CDDP-induced renal injury.
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PMID:Physiological and pharmacological concentrations of melatonin protect against cisplatin-induced acute renal injury. 1222 Mar 31


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