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)

To investigate the effect of gamma-aminobutyric acid (GABA) on acute renal failure, we used a rat model of acute tubular necrosis induced by glycerol. After deprivation of water for 6h, the rats received an injection of 50% glycerol into the muscle of the rear limb at 10 ml/kg body weight. GABA was then administered orally to the rats (100 or 500 mg/kg body weight/day) once every 12h for 3 days. The rats with acute renal failure showed arrested body weight gain and an increase of kidney weight, whereas oral administration of GABA attenuated the physiological changes induced by acute renal failure. However, GABA administration had no significant effect on increased urine volume. Oral administration of GABA at a dose of 100 or 500 mg/kg body weight/day for 3 days significantly improved the markedly elevated levels of blood urea nitrogen and creatinine and the reduced creatinine clearance related to progression of renal failure. Moreover, the rats with acute renal failure exhibited high levels of fractional excretion of sodium (FE(Na)) due to alteration of tubule function following injection of glycerol. However, administration of GABA lowered the FE(Na) levels dose-dependently. Furthermore, urine osmolarity was markedly reduced in control rats with acute renal failure as compared with normal rats, whereas it was significantly increased by administration of GABA at a dose of 500 mg/kg body weight/day. These results indicate that GABA has potential as a therapeutic agent against the renal damage involved in acute renal failure.
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PMID:Protective effect of gamma-aminobutyric acid against glycerol-induced acute renal failure in rats. 1550 Sep 37

To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs.
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PMID:MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice. 1569 64

A 62-year-old male died of colchicine poisoning after accidental ingestion of Colchicum autumnale (meadow saffron). He ate a salad of plant with green leaves regarded as wild garlic (Allium ursinum). A few hours later he developed symptoms of gastroenteritis and was admitted to hospital. In spite of gastric lavage, activated charcoal and supportive measures, multi-organ system failure developed over the next two days. Laboratory analysis showed highly elevated blood concentrations of hepatic enzymes, creatine kinase, lactate dehydrogenase and blood urea nitrogen, as well as leukocytopenia and thrombocytopenia. Mechanical ventilation, dopamine, noradrenaline, crystalloid solutions and fresh frozen plasma were applied but despite treatment the patient died five days after the ingestion. Post-mortem examination revealed hepatic centrilobular necrosis, nephrotoxic acute tubular necrosis, petechial bleeding in fatty tissue, blunt and shortened intestinal villi and cerebral toxic edema. Botanical identification of incriminated plant gave Colchicum autumnale which confirmed colchicine poisoning. Although the accidental ingestion of Colchicum autumnale is rare and to our knowledge only five such cases have been described in detail, this is the second fatal case in Croatia described in the last 3 years.
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PMID:Fatal colchicine poisoning by accidental ingestion of meadow saffron-case report. 1574 68

Organ damage as a consequence of ischaemia and reperfusion (I/R) is a major clinical problem in an acute renal failure and transplantation. Ligands on surfaces of endothelial cells that are exposed due to the ischaemia may be recognized by pattern recognition molecules such as mannan-binding lectin (MBL), inducing complement activation. We examined the contribution of the MBL complement pathway in a bilateral renal I/R model (45 min of ischaemia followed by 24 h of reperfusion), using transgenic mice deficient in MBL-A and MBL-C [MBL double knockout (MBL DKO)] and in wildtype (WT) mice. Kidney damages, which were evaluated by levels of blood urea nitrogen (BUN) and creatinine, showed that MBL DKO mice were significantly protected compared with WT mice. MBL DKO mice, reconstituted with recombinant human MBL, showed a dose-dependent severity of kidney injury increasing to a comparable level to WT mice. Acute tubular necrosis was evident in WT mice but not in MBL DKO mice after I/R, confirming renal damages in WT mice. MBL ligands in kidneys were observed to be present after I/R but not in sham-operated mice. C3a (desArg) levels in MBL DKO mice were decreased after I/R compared with that in WT mice, indicating less complement activation that was correlated with less C3 deposition in the kidneys of MBL DKO mice. Our data implicate a role of MBL in I/R-induced kidney injury.
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PMID:Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. 1588 34

Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats. Forty-five minute renal I/R was induced in uni-nephrectomized rats. Rats were divided into a vehicle group, an olprinone group, and a dibutyril (DB) cAMP group. Olprinone (0.2 microg/kg/minute) infusion began 30 min after reperfusion and continued for 3 h. DBcAMP (5 mg/kg), a stable analog of cAMP, was intraperitoneally administered 5 min after reperfusion to clarify the effect of cAMP in our model. Olprinone reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the outer medulla. Hemodynamic status was not affected by olprinone. I/R-induced a decrease in renal tissue blood flow, an increase in renal vascular permeability, and an enhancement of leukocyte activation, reflected by renal tissue levels of myeloperoxidase activity, and the tissue levels of cytokine-induced neutrophil chemoattractant (an equivalent of human interleukin 8) and tumor necrosis factor-alpha were all significantly decreased by olprinone. Olprinone also increased the renal tissue and plasma levels of cAMP in rats subjected to renal I/R. DBcAMP showed similar effects. Our results indicated that olprinone reduced the I/R-induced acute renal injury, probably by inhibiting leukocyte activation. The effects of olprinone could be explained through its action on cAMP levels.
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PMID:Olprinone reduces ischemia/reperfusion-induced acute renal injury in rats through enhancement of cAMP. 1613 69

Positron emission tomography (PET) is perfectly suited for quantitative imaging of the kidneys, and the recent improvements in detector technology, computer hardware, and image processing software add to its appeal. Multiple positron emitting radioisotopes can be used for renal imaging. Some, including carbon-11, nitrogen-13, and oxygen-15, can be used at institutions with an on-site cyclotron. Other radioisotopes that may be even more useful in a clinical setting are those that either can be obtained from radionuclide generators (rubidium-82, copper-62) or have a sufficiently long half-life for transportation (fluorine-18). The clinical use of functional renal PET studies (blood flow, glomerular filtration rate) has been slow, in part because of the success of concurrent technologies, including single-photon emission computed tomography (SPECT) and planar gamma camera imaging. Renal blood flow studies can be performed with O-15-labeled water, N-13-labeled ammonia, rubidium-82, and copper-labeled PTSM. With these tracers, renal blood flow can be quantified using a modified microsphere kinetic model. Glomerular filtration can be imaged and quantified with gallium-68 EDTA or cobalt-55 EDTA. Measurements of renal blood flow with PET have potential applications in renovascular disease, in transplant rejection or acute tubular necrosis, in drug-induced nephropathies, ureteral obstruction, before and after revascularization, and before and after the placement of ureteral stents. The most important clinical application for imaging glomerular function with PET would be renovascular hypertension. Molecular imaging of the kidneys with PET is rather limited. At present, research is focused on the investigation of metabolism (acetate), membrane transporters (organic cation and anion transporters, pepT1 and pepT2, GLUT, SGLT), enzymes (ACE), and receptors (AT1R). Because many nephrological and urological disorders are initiated at the molecular and organelle levels and may remain localized at their origin for an extended period of time, new disease-specific molecular probes for PET studies of the kidneys need to be developed. Future applications of molecular renal imaging are likely to involve studies of tissue hypoxia and apoptosis in renovascular renal disease, renal cancer, and obstructive nephropathy, monitoring the molecular signatures of atherosclerotic plaques, measuring endothelial dysfunction and response to balloon revascularization and restenosis, molecular assessment of the nephrotoxic effects of cyclosporine, anticancer drugs, and radiation therapy. New radioligands will enhance the staging and follow-up of renal and prostate cancer. Methods will be developed for investigation of the kinetics of drug-delivery systems and delivery and deposition of prodrugs, reporter gene technology, delivery of gene therapy (nuclear and mitochondrial), assessment of the delivery of cellular, viral, and nonviral vectors (liposomes, polycations, fusion proteins, electroporation, hematopoietic stems cells). Of particular importance will be investigations of stem cell kinetics, including local presence, bloodborne migration, activation, seeding, and its role in renal remodeling (psychological, pathological, and therapy induced). Methods also could be established for investigating the role of receptors and oncoproteins in cellular proliferation, apoptosis, tubular atrophy, and interstitial fibrosis; monitoring ras gene targeting in kidney diseases, assessing cell therapy devices (bioartificial filters, renal tubule assist devices, and bioarticial kidneys), and targeting of signal transduction moleculas with growth factors and cytokines. These potential new approaches are, at best, in an experimental stage, and more research will be needed for their implementation.
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PMID:Future direction of renal positron emission tomography. 1635 95

Despite advances in health care, morbidity and mortality associated with acute renal failure (ARF) remain high. This study determined the frequency and etiology of ARF in hospitalized patients in Saudi Arabia over 2 years. Of the 150 cases of ARF, 38.0% were community-acquired and 62.0% hospital-acquired. The main cause was acute tubular necrosis (ATN) in 93 patients, due to sepsis (24.7%), ischaemia (12.7%), rhabdomyolysis (mainly from road traffic accidents) (10.7%), drugs (7.3%) and malaria and snake-bites (4.6%). Overall, 40% died, 48% made a full recovery and 1 patient (0.7%) became dialysis-dependant. Factors associated with poor prognosis were: age 60+ years, community-acquired ARF, peak blood urea nitrogen > 160 mg/dL, duration of ARF > 1 week, need for dialysis and associated chronic liver disease.
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PMID:Epidemiology of acute renal failure in hospitalized patients: experience from southern Saudi Arabia. 1645 May 38

Subcutaneous injection of sodium arsenite (NaAs, 12.5 mg/kg) into BALB/c [wild-type (WT)] mice causes acute renal dysfunction characterized by severe hemorrhages, acute tubular necrosis, and cast formation, with increases in serum blood urea nitrogen and creatinine levels. Concomitant enhancement in intrarenal interferon (IFN)-gamma expression prompted us to examine its roles in this pathology. IFN-gamma-deficient (IFN-gamma-/-) mice exhibited higher serum blood urea nitrogen and creatinine levels and exaggerated histopathological changes, compared with WT mice. Eventually, IFN-gamma-/- mice exhibited a high mortality (87.5%) within 24 hours after NaAs challenge, whereas most WT mice survived. The intrarenal arsenic concentration was significantly higher in IFN-gamma-/- mice later than 10 hours after NaAs treatment, with attenuated intrarenal expression of multidrug resistance-associated protein (MRP) 1, a main transporter for NaAs efflux, compared with WT mice. NF-E2-related factor (Nrf) 2 protein, a transcription factor crucial for MRP1 gene expression, was similarly increased in the kidneys of both strains of mice after NaAs treatment. In contrast, the absence of IFN-gamma augmented transforming growth factor-beta-Smad3 signal pathway and eventually enhanced the expression of activating transcription factor 3, which is presumed to repress Nrf2-mediated MRP1 gene expression. Thus, IFN-gamma can protect against NaAs-induced acute renal injury, probably by maintaining Nrf2-mediated intrarenal MRP1 gene expression.
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PMID:Interferon-gamma plays protective roles in sodium arsenite-induced renal injury by up-regulating intrarenal multidrug resistance-associated protein 1 expression. 1700 72

Previously, we have provided evidence that cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) are involved in the oxidation of S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) in rabbit liver microsomes to yield the reactive metabolite TCVC sulfoxide (TCVCS). Because TCVC is a known nephrotoxic metabolite of tetrachloroethylene, the nephrotoxic potential of TCVCS in rats and TCVCS formation in rat liver and kidney microsomes were investigated. At 5 mM TCVC, rat liver microsomes formed TCVCS at a rate nearly 5 times higher than the rate measured with rat kidney microsomes, whereas at 1 mM TCVC only the liver activity was detectable. TCVCS formation in liver and kidney microsomes was dependent upon the presence of NADPH and was inhibited by the addition of methimazole or 1-benzylimidazole, but not superoxide dismutase, catalase, KCN, or deferoxamine, consistent with the involvement of both FMOs and P450s. Rats given TCVCS at 230 micromol/kg i.p. exhibited acute tubular necrosis at 2 and 24 h after treatment, and they had elevated blood urea nitrogen levels at 24 h, whereas TCVC was a much less potent nephrotoxicant than TCVCS. Furthermore, pretreatment with aminooxyacetic acid enhanced TCVC toxicity. In addition, reduced nonprotein thiol concentrations in the kidney were decreased by nearly 50% 2 h after TCVCS treatment compared with saline-treated rats, whereas the equimolar dose of TCVC had no effect on kidney nonprotein thiol status. No significant lesions or changes in nonprotein thiol status were observed in liver with either TCVC or TCVCS. Collectively, the results suggest that TCVCS may play a role in TCVC-induced nephrotoxicity.
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PMID:S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant. 1734 24

The term pre-renal azotemia (or on occasion 'pre-renal renal failure') is frequently used in textbooks and in the literature to indicate an acute syndrome characterized by the presence of an increase in the blood concentration of nitrogen waste products (urea and creatinine). This syndrome is assumed to be due to loss of glomerular filtration rate but is not considered to be associated with histopathological renal injury. Thus, the term is used to differentiate 'functional' from 'structural' acute kidney injury (AKI) where structural renal injury is taken to indicate the presence of so-called acute tubular necrosis (ATN). This paradigm is well entrenched in nephrology and medicine. However, growing evidence from experimental animal models, systematic analysis of the human and experimental literature shows that this paradigm is not sustained by sufficient evidence when applied to the syndrome of septic AKI, especially in critically ill patients. In such patients, several assumptions associated with the 'pre-renal azotemia paradigm' are violated. In particular, there is no evidence that ATN is the histopathological substrate of septic AKI, there is no evidence that urine tests can discriminate 'functional' from 'structural' AKI, there is no evidence that any proposed differentiation leads or should lead to different treatments, and there is no evidence that relevant experimentation can resolve these uncertainties. Given that septic AKI of critical illness now accounts for close to 50% of cases of severe AKI in developed countries, these observations call into question the validity and usefulness of the 'pre-renal azotemia paradigm' in AKI in general.
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PMID:Pre-renal azotemia: a flawed paradigm in critically ill septic patients? 1746 9


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