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1.
J Bras Nefrol ; 44(1): 26-31, 2022.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34424258

RESUMO

INTRODUCTION: Tubular damage is common in glomerular diseases (GD). Glycosuria is a marker of tubular dysfunction and may be used to detect tubular lesion and CKD progression. The aim of this study was to evaluate the prevalence and prognostic value of glycosuria at the time of diagnosis in primary glomerulopathies (PG). METHODS: We conducted a 24-month retrospective study in patients diagnosed with PG in our center between 2009 and 2020. We excluded diabetic patients, use of SGLT2 inhibitors, transplant patients, and secondary GD. Patients were divided in two groups according to their glycosuria status at diagnosis. RESULTS: We studied 115 patients. Global prevalence of glycosuria was 10% (n=11) and membranous nephropathy (MN) had the highest prevalence (n=5, 17.9%). We found that patients with glycosuria had higher serum creatinine (2.4 vs. 1.2 mg/dL, p=0.030), higher albuminuria (4.8 vs. 1.9 g/g, p=0.004), and lower serum albumin (2.3 vs. 3.2 g/dL, p=0.021). We did not find association with histological prognostic factors. At the end of follow-up, patients with glycosuria had higher prevalence of the composite outcome of stage 5D CKD or 50% increase in basal SCr (45.5% vs. 17.3%, p=0.037). In patients with MN, results were similar but we were able to find an association of glycosuria with more severe interstitial fibrosis and tubular atrophy (25.0 vs. 0.0 %, p=0.032). CONCLUSION: Ten percent of our patients with PG have glycosuria. Glycosuria at the time of diagnosis was associated with more severe clinical presentation and worst renal outcome. The association with higher albuminuria suggests that tubular function has an impact on the severity and outcomes of PG.


Assuntos
Glicosúria , Nefropatias , Glicosúria/patologia , Humanos , Prevalência , Prognóstico , Estudos Retrospectivos
2.
Biofactors ; 47(4): 645-657, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33836111

RESUMO

Diabetes is considered one of the most important health emergencies worldwide and Egypt has 8.2 million diabetic patients according to the International Diabetes Federation report in 2017. The objective of this study was to monitor the time-course variation in the metabolic profile of diabetic rats to detect urinary metabolic biomarkers using the metabolomics approach. Type 2 diabetes was induced in male Wistar albino rats using a single intraperitoneal injection of 40 mg/kg of streptozotocin following oral administration of 10% fructose in drinking water for 3 weeks. Then, urine was collected for 24 h from rats at three time points (0, 2, and 4 weeks after confirmation of diabetes), and were analyzed by nuclear magnetic resonance (H1 -NMR), followed by multivariate data analysis. The results from H1 -NMR pointed out that d-glucose, taurine, l-carnitine, l-fucose, 1,5-anhydrosorbitol, and d-galactose levels showed consistent significant variation (p < 0.05) between the positive (diabetic) and negative (normal) controls during the whole experimental period. Also, with the disease progression, myoinositol, and l-phenylalanine levels were significantly altered (p < 0.05) after 2 weeks and this alteration was maintained till the end of the 4-week experimental period in the positive control group. From the results of the present study, it could be concluded that we cannot depend only on glucose levels for prognostic purposes since there are other metabolic disturbances in diabetes which need to be tracked for better disease prognosis.


Assuntos
Diabetes Mellitus Experimental/urina , Glicosúria/urina , Metabolômica/métodos , Animais , Biomarcadores/urina , Carnitina/urina , Análise por Conglomerados , Desoxiglucose/urina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Progressão da Doença , Frutose/administração & dosagem , Fucose/urina , Galactose/urina , Glicosúria/induzido quimicamente , Glicosúria/genética , Glicosúria/patologia , Inositol/urina , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Fenilalanina/urina , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Taurina/urina , Fatores de Tempo
3.
Hum Mol Genet ; 29(12): 2098-2106, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32227112

RESUMO

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.


Assuntos
Diabetes Mellitus Tipo 2/genética , Glicosúria/genética , Complicações na Gravidez/genética , Transportador 2 de Glucose-Sódio/genética , Adolescente , Adulto , Índice de Massa Corporal , Cromossomos Humanos Par 16/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Glicosúria/epidemiologia , Glicosúria/patologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Complicações na Gravidez/patologia , Adulto Jovem
4.
Sci Rep ; 9(1): 15765, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673025

RESUMO

We reported previously that overexpression of heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in renal proximal tubular cells (RPTCs) suppresses angiotensinogen (Agt) expression, and attenuates systemic hypertension and renal injury in diabetic Hnrnpf-transgenic (Tg) mice. We thus hypothesized that deletion of Hnrnpf in the renal proximal tubules (RPT) of mice would worsen systemic hypertension and kidney injury, perhaps revealing novel mechanism(s). Tubule-specific Hnrnpf knockout (KO) mice were generated by crossbreeding Pax8-Cre mice with floxed Hnrnpf mice on a C57BL/6 background. Both male and female KO mice exhibited elevated systolic blood pressure, increased urinary albumin/creatinine ratio, tubulo-interstitial fibrosis and glycosuria without changes in blood glucose or glomerular filtration rate compared with control littermates. However, glycosuria disappeared in male KO mice at the age of 12 weeks, while female KO mice had persistent glycosuria. Agt expression was elevated, whereas sodium-glucose co-transporter 2 (Sglt2) expression was down-regulated in RPTs of both male and female KO mice as compared to control littermates. In vitro, KO of HNRNPF in human RPTCs (HK-2) by CRISPR gRNA up-regulated AGT and down-regulated SGLT2 expression. The Sglt2 inhibitor canagliflozin treatment had no effect on Agt and Sglt2 expression in HK-2 and in RPTCs of wild-type mice but induced glycosuria. Our results demonstrate that Hnrnpf plays a role in the development of hypertension and glycosuria through modulation of renal Agt and Sglt2 expression in mice, respectively.


Assuntos
Glicosúria , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/deficiência , Hipertensão , Túbulos Renais Proximais , Animais , Glicemia/metabolismo , Taxa de Filtração Glomerular , Glicosúria/genética , Glicosúria/metabolismo , Glicosúria/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Camundongos , Camundongos Knockout
5.
Nephrol Dial Transplant ; 34(10): 1731-1738, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982607

RESUMO

BACKGROUND: Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes. METHODS: During the period 1990-92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all-cause death. RESULTS: Glycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49-0.97, P = 0.03). CONCLUSIONS: Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/etiologia , Glicosúria/patologia , Hiperglicemia/complicações , Adulto , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , França/epidemiologia , Taxa de Filtração Glomerular , Glicosúria/epidemiologia , Humanos , Incidência , Masculino
6.
Int. j. morphol ; 37(1): 28-35, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-990000

RESUMO

SUMMARY: There is an increasing amount of evidence that supports the diabetic complications of the central nervous system structure and function. The cerebellum, which is one of the primary structure derived from the hindbrain, plays an important role in motor control, motor coordination, and non-motor functions, such as cognitive processing. The synapse is a critical structure that regulates neuronal communication, and well-defined afferent and efferent fibre connections in the cerebellum help in maintaining the proper working order. Thus, the present study sought to investigate the long-term effects of diabetes-induced synaptopathy in the cerebellum, using both histological and ultrastructural studies. Twenty Sprague-Dawley male rats were divided randomly into control and diabetic groups, and diabetes was then induced through a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). Six month later, the rats were sacrificed and the cerebellum was removed. Light and electron microscopic examinations showed a degeneration of Purkinje cells (Neuron purkinjense) with shrunken cells, pyknotic nuclei, and synaptopathy, including the reduction in synapse density, number of synaptic vesicles, and maturation of synapses in the molecular layer of diabetic cerebellum. The disruptions in synaptic profiles, which observed in the diabetic condition, could be related to cerebellar dysfunction, thus leading to the defects in coordinated movement, balance, as well as cognitive learning and memory.


RESUMEN: Actualmente existe una creciente evidencia que apoya las complicaciones diabéticas de la estructura y función del sistema nervioso central. El cerebelo, una de las estructuras primarias del cerebro posterior, desempeña un papel importante en el control motor, la coordinación motora y las funciones no motoras, tanto como en el procesamiento cognitivo. La sinapsis es una estructura crítica que regula la comunicación neuronal y las conexiones de fibras aferentes y eferentes bien definidas en el cerebelo, ayudan a mantener el funcionamiento correcto. Por lo tanto, en el presente estudio se investigaron los efectos a largo plazo de la sinaptopatía inducida por la diabetes en el cerebelo, utilizando estudios histológicos y ultraestructurales. Veinte ratas SpragueDawley macho se dividieron al azar en grupos de control y diabetes, se indujó la diabetes a través de una inyección intraperitoneal única de estreptozotocina (60 mg / kg de peso corporal). Seis meses después, se sacrificaron las ratas y se extrajo el cerebelo. Los exámenes de microscopías óptica y electrónica mostraron una degeneración de las neuronas purkinjenses (células de Purkinje), con células reducidas, núcleos picnóticos y sinaptopatía, como también la densidad reducida de sinapsis, el número de vesículas sinápticas y la maduración de las sinapsis en la capa molecular del cerebelo de las ratas diabéticas. Las interrupciones en los perfiles sinápticos, que se observaron en la condición diabética, podrían estar relacionadas con la disfunción cerebelosa, lo que lleva a defectos en el movimiento coordinado, el equilibrio, así como al aprendizaje cognitivo y la memoria.


Assuntos
Animais , Masculino , Ratos , Sinapses/patologia , Cerebelo/patologia , Diabetes Mellitus Experimental/patologia , Células de Purkinje/patologia , Redução de Peso , Ratos Sprague-Dawley , Glicosúria/patologia , Hiperglicemia/patologia , Microscopia/métodos
7.
PLoS One ; 11(1): e0144640, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26741142

RESUMO

Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-ß1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Glicosúria/metabolismo , Hipertensão Renal/metabolismo , Hipoglicemiantes/farmacologia , Proteinúria/metabolismo , Insuficiência Renal Crônica/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Expressão Gênica , Taxa de Filtração Glomerular , Glicosúria/tratamento farmacológico , Glicosúria/etiologia , Glicosúria/patologia , Humanos , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/etiologia , Hipertensão Renal/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Nefrectomia/efeitos adversos , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Proteinúria/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Falha de Tratamento
8.
Toxicol Pathol ; 41(5): 761-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23076036

RESUMO

We have previously reported that dental caries progress in spontaneously and chemically induced diabetic rodent models. The aim of this study was to clarify the relationship between hyperglycemia and dental caries by evaluating the preventive effect of glycemic control with insulin on the progression of the lesions in diabetic rats. Male WBN/KobSlc rats aged 15 weeks were divided into groups of spontaneously diabetic rats (intact group), spontaneously diabetic rats with insulin treatment (INS group), alloxan-induced prolonged diabetic rats (AL group), and alloxan-induced prolonged diabetic rats with insulin treatment (AL + INS group). The animals were killed at 90 weeks of age, and their oral tissue was examined. Dental caries and periodontitis were frequently detected in the intact group, and the lesions were enhanced in the AL group (in which there was an increased duration of diabetes). Meanwhile, glycemic control with insulin reduced the incidence and severity of dental caries and periodontitis in the INS group, and the effects became more pronounced in the AL + INS group. In conclusion, glycemic control by insulin prevented the progression of dental caries and caries-related periodontitis in the diabetic rats.


Assuntos
Cárie Dentária/metabolismo , Cárie Dentária/prevenção & controle , Diabetes Mellitus Experimental/patologia , Hiperglicemia/tratamento farmacológico , Insulina/uso terapêutico , Periodontite/prevenção & controle , Animais , Glicemia/metabolismo , Reabsorção Óssea/patologia , Cárie Dentária/diagnóstico por imagem , Cárie Dentária/patologia , Diabetes Mellitus Experimental/sangue , Progressão da Doença , Gengiva/patologia , Glicosúria/metabolismo , Glicosúria/patologia , Histocitoquímica , Masculino , Mandíbula/patologia , Periodontite/metabolismo , Periodontite/patologia , Radiografia , Ratos
9.
Eur J Pharmacol ; 662(1-3): 1-8, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21549692

RESUMO

Recently, we reported that monosodium glutamate-treated mice (MSG mice) developed severe hyperlipidemia and diabetes mellitus and several complications of obesity. MSG mice acquired fatty livers and subsequently underwent changes that are characteristic of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In the present study, the effects of bezafibrate on obesity, diabetes mellitus, and NAFLD/NASH were examined in MSG mice. A single dose of MSG (4 mg/g) was administered subcutaneously to neonatal male mice within 24h of birth. Bezafibrate was mixed into the normal feed for 8 weeks. The weight and body mass index of MSG mice increased significantly despite the unchanged intake of food. Triglyceride and total cholesterol levels in blood, visceral adipose tissue, and interscapular adipose tissue rose significantly. In the livers of MSG mice, moderate centrilobular microvesicular steatosis, ballooning degeneration with Mallory bodies, and scattered infiltration of neutrophils and lymphocytes were observed. Centrilobular hepatocytes were 4-hydroxynonenal-positive in MSG mice. Bezafibrate ameliorated the severity of diabetes mellitus, hyperinsulinemia, and hyperlipidemia. Adiponectin and leptin concentrations in blood improved, and the accumulation of visceral fat was inhibited. The expression of acyl-CoA oxidase, a beta-oxidation gene, and carnitine palmitoyl transferase, which regulates lipid metabolism, increased markedly on administration of bezafibrate. The liver pathology in MSG mice also improved with bezafibrate; specifically, macro- and microvesicles in hepatocytes nearly disappeared, and NAFLD activity score improved. It is concluded that bezafibrate inhibits the accumulation of visceral fat, following amelioration of hyperlipidemia, in MSG-induced obese mice, due to improvements in diabetes mellitus, fatty liver, and NAFLD.


Assuntos
Bezafibrato/farmacologia , Fígado Gorduroso/tratamento farmacológico , Hipolipemiantes/farmacologia , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Glutamato de Sódio/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Bezafibrato/uso terapêutico , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Glicosúria/induzido quimicamente , Glicosúria/tratamento farmacológico , Glicosúria/metabolismo , Glicosúria/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Leg Med (Tokyo) ; 13(4): 196-200, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21377395

RESUMO

We describe an autopsy case in which a patient with diabetic ketoacidosis (DKA) was found in a head-down position. A female in her late 70s was found dead in her home in a supine position on the kitchen floor. The upper part of her body was hanging down over the edge of the kitchen floor to the backyard through the open window. External examination revealed congestion of the head and upper region of the face and neck. There were numerous petechiae on the superior palpebral conjunctivae and upper part of the oral mucosa. On internal examination, extensive hemorrhages in the subcutaneous fat tissues and muscles were observed at the upper part of the neck, although there were no external injuries on the neck. Histopathological examination revealed that hemorrhages were accompanied with infiltration of polymorphonuclear leukocytes both within and around the hemorrhages on the neck skin. Nodular glomerulosclerosis and many fat droplets in the cytoplasm of proximal tubule cells were found in the kidney. Postmortem blood analysis showed acetone (204.2 µg/ml), HbA1c (10.8%), acetoacetate (<2.0 µmol/l), 3-hydroxybutyrate (11,844 µmol/l), blood urea nitrogen (128.9 mg/dl), and creatinine (3.11 mg/dl). The glucose and acetone levels in the urine were 876.7 mg/dl and 201.4 µg/ml, respectively, suggesting that she suffered severe DKA. However, since hemorrhage of the neck could have developed only when she was still alive, asphyxia should have arisen antemortem. Based on these findings, we concluded that the direct cause of her death is positional asphyxia, which was resulted from DKA. It is difficult to diagnose the cause of death when the victim is in an unusual posture. To confirm a suspicion of positional asphyxia, photographs of the undisturbed scene are useful in addition to a precise autopsy and accurate examinations.


Assuntos
Asfixia/etiologia , Cetoacidose Diabética/diagnóstico , Postura , Ácido 3-Hidroxibutírico/sangue , Acetona/análise , Idoso , Asfixia/diagnóstico , Nefropatias Diabéticas/patologia , Feminino , Patologia Legal , Hemoglobinas Glicadas/análise , Glicosúria/patologia , Hemorragia/patologia , Humanos , Rim/patologia , Pescoço , Músculos do Pescoço/patologia , Neutrófilos/patologia , Púrpura/patologia
11.
Exp Anim ; 59(4): 407-19, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20660987

RESUMO

In order to examine the influence of obesity on metabolic disorder and liver pathogenesis of the Fatty Liver Shionogi (FLS) mouse, which develops hereditary fatty liver and spontaneous liver tumors, we established a new congenic strain named FLS-Lep(ob). The Lep(ob) gene of the C57BL/6JWakShi (B6)-Lep(ob)/Lep(ob) mouse was transferred into the genome of the FLS mouse, by backcross mating. FLS-Lep(ob)/Lep(ob) mice were maintained by intercrossing between Lep(ob)-heterozygous littermates. The FLS-Lep(ob)/Lep(ob) mice of both sexes developed remarkable hyperphagia, obesity and type 2 diabetes mellitus. At 12 weeks of age, glucosuria was detected in all male and female FLS-Lep(ob)/Lep(ob) mice. Biochemical examination demonstrated that the FLS-Lep(ob)/Lep(ob) mice have severe hyperlipidemia and hyperinsulinemia. The livers of FLS-Lep(ob)/Lep(ob) mice showed microvesicular steatosis and deposition of large lipid droplets in hepatocytes throughout the lobules. The steatohepatitis-like lesions including the multifocal mononuclear cell infiltration and clusters of foamy cells were observed earlier in FLS-Lep(ob)/ Lep(ob) mice than in FLS mice. B6-Lep(ob)/Lep(ob) mice did not show hepatic inflammatory change. Furthermore, FLS-Lep(ob)/Lep(ob) mice developed multiple hepatic tumors including hepatocellular adenomas and carcinomas following steatohepatitis. In conclusion, the FLS-Lep(ob)/Lep(ob) mice developed steatohepatitis and hepatic tumors following hepatic steatosis. The FLS-Lep(ob)/Lep(ob) mouse with obesity and type 2 diabetes mellitus might be a useful animal model for human non-alcoholic steatohepatitis (NASH).


Assuntos
Adenoma de Células Hepáticas/genética , Carcinoma Hepatocelular/genética , Fígado Gorduroso/genética , Resistência à Insulina/genética , Neoplasias Hepáticas/genética , Adenoma de Células Hepáticas/sangue , Adenoma de Células Hepáticas/patologia , Animais , Carcinoma Hepatocelular/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Teste de Tolerância a Glucose , Glicosúria/sangue , Glicosúria/genética , Glicosúria/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Hiperlipidemias/sangue , Hiperlipidemias/genética , Hiperlipidemias/patologia , Leptina/genética , Leptina/metabolismo , Lipídeos/análise , Fígado/química , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/genética , Obesidade/patologia , RNA Mensageiro/metabolismo
12.
Toxicol Pathol ; 38(4): 658-65, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20448086

RESUMO

This was a study of the microscopic, ultrastructural, immunohistochemical, and enzyme cytochemical features of giant eosinophilic granules encountered in pancreatic acinar cells of alloxan-induced diabetic rats. Seven male F344 rats with diabetes induced by a single i.v. dose of alloxan were sacrificed after twenty-five weeks of treatment. Histologically, the pancreatic acini were diffusely atrophied, and the islets showed marked atrophy or had disappeared, and giant eosinophilic granules and small vacuoles were observed in almost all acinar cells. The eosinophilic granules showed negative reactions for periodic acid-Schiff (PAS) and acid phosphatase, as well as fat stains such as Nile blue, Oil red O, and Sudan III. Ultrastructurally, the giant eosinophilic granules were huge structures surrounded by a double membrane containing many irregular cristae. A large amount of small lipid droplets was also apparent in the basal area of the acinar cells. Immunohistochemical analysis of prohibitin, a kind of protein located in the mitochondrial inner membrane, was partially positive in the marginal area of some giant eosinophilic granules, but negative for the central area. The enzyme activity for succinic dehydrogenase (SDH), one of the mitochondrial enzymes, showed a localizing pattern similar to that of prohibitin. These findings confirmed that the giant eosinophilic granules in the exocrine pancreas of alloxan-induced diabetic rats were giant mitochondria.


Assuntos
Diabetes Mellitus Experimental/patologia , Mitocôndrias/patologia , Pâncreas Exócrino/patologia , Aloxano , Animais , Glicemia/metabolismo , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Eosinófilos/metabolismo , Glicosúria/sangue , Glicosúria/patologia , Histocitoquímica , Masculino , Microscopia Eletrônica , Mitocôndrias/metabolismo , Pâncreas Exócrino/ultraestrutura , Proibitinas , Ratos , Ratos Endogâmicos F344 , Proteínas Repressoras/metabolismo , Vacúolos/metabolismo , Vacúolos/ultraestrutura
13.
Toxicol Pathol ; 37(6): 790-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19700660

RESUMO

Alloxan-induced diabetic rats frequently exhibit proliferative lesions of squamous hyperplasia accompanied by chronic inflammation and Candida albicans infection in the forestomach, and some lesions progress to squamous cell carcinoma (SCC). Candida infection causes not only hyperplastic changes with inflammation but might also lead to SCC in human oral mucosa. Thus, the present study was conducted to examine the effects of the antifungal agent itraconazole (ITCZ) on proliferative and inflammatory changes of the forestomach in alloxan-induced diabetic WBN/Kob rats. Diabetes was induced by alloxan at fifteen weeks of age. Rats were allocated to three groups at forty-five weeks of age and were given ITCZ by gavage 0 (vehicle control), 5, and 10 mg/kg/day for four weeks, and they were sacrificed at the sixty-fifth week of age. Mucosal hyperplastic changes were consistently accompanied by inflammation and Candida infections in the 0 mg/kg group. These lesions were reduced by ITCZ (0 mg/kg; 100%, 5 mg/kg; 53.5%, 10 mg/kg; 61.5%). Squamous cell carcinoma was detected in three rats from the 0 mg/kg, but only one rat from the 10 mg/kg dose groups in this study. Itraconazole reduced the degree of mucosal hyperplasia, inflammatory changes, and Candida infection. Therefore, C. albicans infection was an important factor in pathogenesis of mucosal proliferation and inflammation.


Assuntos
Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Mucosa Gástrica/efeitos dos fármacos , Itraconazol/farmacologia , Animais , Candida albicans , Candidíase/metabolismo , Candidíase/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Experimental/patologia , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Glicosúria/tratamento farmacológico , Glicosúria/metabolismo , Glicosúria/microbiologia , Glicosúria/patologia , Histocitoquímica , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/microbiologia , Hiperglicemia/patologia , Hiperplasia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos
14.
Artigo em Russo | MEDLINE | ID: mdl-20050166

RESUMO

The treatment of diabetic patients with pyonecrotic lesions in the lower extremities requires prolonged reflexo-segmental balneophysiotherapy to normalize functions of the nerve centres. Curative volcanic mud solutions (15-24 g/l) enriched with organic and nonorganic biologically active compounds from volcanic deposits in Azerbaijan were used for the first time to treat such patients. Peloids were applied to the lumbar region (location of sympathetic nerve nodes) and the lower legs above and beneath the affected sites. The patients were subjected to 12-15 seances of peloidotherapy (at 40-41 degrees Celsius) each lasting 20-30 minutes. The treatment was preceded by wound sanation using the standard procedure and a course of antibiotic therapy based on individual antibiotocograms. A total of 86 daibetic patients with leg gangrene underwent rheovasographic thermovision examination that revealed enhanced blood supply to the affected extremities under the action of the applied peloids. Peloidotherapy resulted in the normalization of blood and urine glucose levels in 53 (63%) of the patients. Simultaneously, the doses of medicamentous therapy could be lowered. Wound and ulcer healing was completed in the majority of the patients (86%) by the end of balneophysiotherapy when fresh granulation tissue began to develop and signs of oedema to disappear. These patients no longer needed amputation.


Assuntos
Glicemia/análise , Complicações do Diabetes , Gangrena , Glicosúria/urina , Peloterapia , Antibacterianos/administração & dosagem , Glicemia/metabolismo , Complicações do Diabetes/sangue , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Complicações do Diabetes/urina , Feminino , Gangrena/sangue , Gangrena/patologia , Gangrena/terapia , Gangrena/urina , Glucose/metabolismo , Glicosúria/sangue , Glicosúria/patologia , Glicosúria/terapia , Temperatura Alta , Humanos , Extremidade Inferior/patologia , Masculino , Cicatrização
15.
J Appl Toxicol ; 27(2): 189-94, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17154277

RESUMO

Organophosphate (OP) poisoning, which inhibits cholinesterase activity, leads to severe cholinergic symptoms. Effective and quick management of these symptoms is considered critical to the clinical outcome. Acute renal damage following exposure to OP insecticides has been reported. Similar complications might occur following exposure to OP nerve agents, however, this subject has been studied only sporadically. In the present study, the effect of the nerve agent sarin on renal function was examined in rats. A single dose of sarin ( approximately 0.9 LD(50)) led to a significant reduction (of 45%) in renal function during the first 2 days post exposure, as exhibited by evaluation of the glomerular filtration rate, through measuring the clearance of ( 99m)Tc-DTPA. The urine volume was reduced by 50%, the urine specific gravity increased to 104% of the control value and massive hematuria and glucosuria were recorded 24-48 h post exposure. In addition, around 60% decrease in urine electrolytes was monitored during the first 2 days following exposure, with a recovery after 8 days. Post mortem gross inspection of the bladder, 24 h post exposure, revealed severe edema and hemorrhage. Treatment with the muscarinic antagonist atropine and the oxime TMB-4, at excessive doses administered 1 min post exposure, did not prevent most renal impairments. It has been concluded that sarin caused an acute renal dysfunction, possibly accompanied by bladder damage. These impairments were reversible, recovered spontaneously within 3-8 days, and were probably related to the state of shock and hypovolemia caused by the poisoning. However, if renal impairments are left unattended, they might contribute to the overall toxic manifestation and as a result aggravate the clinical state of intoxicated casualties.


Assuntos
Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Sarina/toxicidade , Animais , Antídotos/farmacologia , Atropina/farmacologia , Reativadores da Colinesterase/farmacologia , Glicosúria/induzido quimicamente , Glicosúria/patologia , Hematúria/induzido quimicamente , Hematúria/patologia , Rim/fisiopatologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Tempo , Trimedoxima/farmacologia , Urinálise , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
16.
Exp Brain Res ; 166(2): 220-9, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16034568

RESUMO

The R6/2 transgenic mouse model of Huntington's disease (HD) develops a progressive neurological phenotype that involves severe motor and cognitive dysfunctions. Although not a cardinal sign, diabetes has been described in R6/2 mice. It is not clear, however, whether the diabetes contributes to the HD-like phenotype of R6/2 mice. In our study we found that the severity of diabetes in R6/2 mice was associated with the progressive formation of ubiquinated inclusions in pancreatic beta cells. Diabetes is dissociated from early motor and cognitive dysfunctions and did not correlate with motor impairment and survival of R6/2 mice. However, chronic behavioural testing (at a level higher than that which is reported to improve several aspects of the R6/2 phenotype) exacerbated the onset of diabetes. Pharmacological treatment of the diabetes was attempted using two oral hypoglycaemic agents commonly used by diabetics. The mice responded acutely to glibenclamide (which induces exocytosis of insulin) but not to rosiglitazone (which induces sensitization to insulin). This supports the suggestion that the diabetes in R6/2 mice is caused by an impairment in insulin release rather than insulin insensitivity. However, chronic treatment with these hypoglycaemic agents had no effect on either the course of the diabetes or the disease in R6/2 mice.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Glibureto/farmacologia , Doença de Huntington/complicações , Hipoglicemiantes/farmacologia , Administração Oral , Animais , Comportamento Animal , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Exocitose/efeitos dos fármacos , Intolerância à Glucose/genética , Intolerância à Glucose/patologia , Glicosúria/tratamento farmacológico , Glicosúria/genética , Glicosúria/patologia , Doença de Huntington/genética , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Rosiglitazona , Tiazolidinedionas/farmacologia
17.
Arch Toxicol ; 74(12): 745-54, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11305776

RESUMO

Overdosing of colloidal bismuth subcitrate (CBS), used to treat peptic ulcers and Helicobacter pylori infections, has been reported to result in serious, though reversible, nephrotoxicity in humans. However, little is known about the nature of the renal damage induced by bismuth (Bi), and no well-described experimental model exists. Single large oral CBS doses (0.75, 1.5, and 3.0 mmol Bi/kg) were administered to three groups of 20 female Wistar rats. A control group (n = 20) received only the vehicle. Standard kidney function parameters, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and the Bi content were monitored in blood, urine, liver, and kidneys for 14 days. A dose of 3.0 mmol Bi/kg, 100 times the daily therapeutic dose, caused kidney damage within 6 h as detected by proteinuria, glucosuria, and elevated plasma urea and plasma creatinine levels. The kidneys of all animals, except two that died, recovered functionally within 10 days. At a dose of 1.5 mmol Bi/kg, clinical parameters changed less and normalized within 48 h, whereas a dose of 0.75 mmol Bi/kg induced no changes. Histological evaluation revealed that the S3 tubular segment necrotized first with additional necrotization of the S1/S2 segment when more Bi was absorbed. The lesions were accompanied by interstitial infiltrates of CD45+ leukocytes. In summary, we developed a rat model for Bi-induced reversible nephropathy. A large single oral overdose of CBS administered to Wistar rats led to damage to the proximal tubule, especially in the last segment.


Assuntos
Nefropatias/induzido quimicamente , Compostos Organometálicos/toxicidade , Acetilglucosaminidase/urina , Administração Oral , Animais , Creatinina/sangue , Relação Dose-Resposta a Droga , Feminino , Glicosúria/induzido quimicamente , Glicosúria/patologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Proteinúria/induzido quimicamente , Proteinúria/patologia , Ratos , Ratos Wistar , Ureia/sangue
18.
Exp Anim ; 48(3): 181-9, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10480023

RESUMO

By the selective breeding of obese male mice of the ddY strain and using indices of the heavy body weight and appearance of urinary glucose, we established two inbred strains in 1992: one with obesity and urinary glucose (Tsumura, Suzuki, Obese Diabetes: TSOD) and the other without them (Tsumura, Suzuki, Non Obesity: TSNO). The male TSOD mice constantly showed signs of obesity and urinary glucose with increases in food and water intake, body weight and some fat weight. The body mass index (BMI) clearly showed moderate obesity. Increases in the levels of diabetic blood parameters (glucose, insulin and lipids) were also found in males, in which the levels of blood glucose and insulin were high to the ages past the growth peak. In the histological studies, pancreatic islets of the TSOD males were found hypertrophic without any signs of insulitis or fibrous formation. Among these diabetic characteristics, some of which were similar to the reported models of non-insulin-dependent diabetes mellitus (NIDDM), the stable appearances of the hyperglycemia, the hyperinsulinemia and the hypertrophy of pancreatic islets to the ages past the growth peak were the prominent features. In these respect the TSOD mouse may be a useful model for researching the mechanisms of human diabetes and its complications.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Modelos Animais de Doenças , Glicosúria/genética , Hiperinsulinismo/genética , Obesidade , Animais , Glicemia/análise , Colesterol/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/análise , Glicosúria/sangue , Glicosúria/patologia , Hiperinsulinismo/sangue , Hiperinsulinismo/patologia , Hipertrofia , Imuno-Histoquímica , Endogamia , Insulina/análise , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Linhagem , Gravidez , Triglicerídeos/sangue
19.
Braz J Med Biol Res ; 31(5): 633-7, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9698767

RESUMO

There are doubts about the presence of glycosuria and the progress of glomerular disease. Some reports suggest that glycosuria could be an index of a more severe tubulointerstitial lesion. We investigated the presence of glycosuria in 60 patients with primary glomerular diseases: 17 patients (28%) had glycosuria and 43 patients (72%) were glycosuria free. The two groups were similar in age, arterial pressure and sex. Serum creatinine was higher in patients with glycosuria (2.0 +/- 1.7 vs 1.3 +/- 0.9 mg/dl, P < 0.05). The protein excretion rate was 7.5 +/- 3.7 vs 5.3 +/- 4.2 g/day (P > 0.05) in patients with and without glycosuria, respectively, while serum albumin was lower in patients with glycosuria (1.7 +/- 0.6 vs 2.7 +/- 1.0 g/dl, P < 0.05). Several histological forms were present in the group with glycosuria, with membraneous glomerulonephritis being the most frequent. Histological evidence of tubular atrophy and interstitial fibrosis prevailed in patients with glycosuria, suggesting a poor prognosis for these patients. We may conclude that the presence of glycosuria in patients with glomerular disease is associated with more pronounced tubular atrophy and interstitial fibrosis and therefore imply a poorer prognosis.


Assuntos
Glomerulonefrite/patologia , Glicosúria/patologia , Túbulos Renais/patologia , Adulto , Feminino , Glomerulonefrite Membranosa/patologia , Humanos , Rim/patologia , Masculino , Prognóstico , Estudos Retrospectivos
20.
Chem Res Toxicol ; 11(7): 750-7, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9671537

RESUMO

Hexachlorobuta-1,3-diene (HCBD) is nephrotoxic in rodents. Its toxicity is based upon a multistep bioactivation pathway. Conjugation with glutathione by glutathione S-transferases to form (E)-S-(1,2,3,4,4-pentachlorobutadienyl)-L-glutathione (PCBG), further processing to the corresponding cysteine S-conjugate, and finally processing to a reactive thioketene are thought to be responsible for the observed nephrotoxic effects. A novel metabolite, identified as (E)-N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine sulfoxide (N-AcPCBC-SO), was described after administration of [14C]HCBD to male Wistar rats. This metabolite is formed by sulfoxidation of N-acetyl-S-(1,2,3,4, 4-pentachlorobutadienyl)-L-cysteine (N-AcPCBC) mediated by cytochrome P450 3A and has been found to be cytotoxic to proximal tubular cells in vitro without activation by beta-lyase. In rats, given HCBD in vivo, only one diastereomer of the sulfoxide is excreted; however, in rat hepatic microsomes two diastereomers, (R)- and (S)-N-AcPCBC-SO, are formed. This study focuses on the mechanisms responsible for this discrepancy and on a possible contribution of N-AcPCBC-SO to the nephrotoxicity of HCBD in vivo. (R,S)-N-AcPCBC-SO (1:1 mixture of both diastereomers) and N-acetyl-alpha-methyl-S-(1,2,3,4,4-pentachlorobutadienyl)-d, L-cysteine sulfoxide (alpha-Me-N-AcPCBC-SO) were administered iv to male and female Wistar rats (20, 40, and 80 micromol/kg of body weight). alpha-Me-N-AcPCBC-SO cannot be cleaved by cysteine conjugate beta-lyase even if alpha-Me-N-AcPCBC-SO is deacetylated by acylases. Excretion of gamma-glutamyltranspeptidase, protein, and glucose in the urine, indicative for kidney damage, and histopathological examination of the kidneys showed marked differences in the renal damage in male and female rats after application of N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO. Necroses of the kidney tubules were only found in male, but not female, rats. Major sex-specific differences were observed in the elimination of sulfoxides; the (R)-isomer was excreted in a 5-10-fold excess to the (S)-isomer after application of (R,S)-N-AcPCBC-SO. After purification, both isomers were administered to male rats resulting in the urinary excretion of (R)-N-AcPCBC-SO after giving the (R)-isomer; treatment with (S)-N-AcPCBC-SO, however, revealed the formation of (S)-N-acetyl-S-(2-glycinylcystein-S-yl-1,3,4, 4-tetrachlorobutadienyl)-L-cysteine. The results show major sex-specific differences in the nephrotoxic potency of N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO. However, both N-AcPCBC-SO and alpha-Me-N-AcPCBC-SO are nephrotoxic in males, suggesting the formation of a vinyl sulfoxide as an additional, beta-lyase-independent mechanism in HCBD-caused nephrotoxicity.


Assuntos
Butadienos/farmacocinética , Butadienos/toxicidade , Cisteína/análogos & derivados , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/toxicidade , Sulfóxidos/farmacocinética , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cisteína/farmacocinética , Cisteína/toxicidade , Feminino , Glicosúria/induzido quimicamente , Glicosúria/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Proteinúria/induzido quimicamente , Proteinúria/patologia , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta , Sulfóxidos/toxicidade , gama-Glutamiltransferase/urina
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