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2.
Hum Exp Toxicol ; 20(2): 100-10, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11327510

ABSTRACT

Progressive renal dysfunction in 5/6 nephrectomized (NX) rats can be physiologically divided into three stages, coinciding with morphological stages, after definition of physiological parameters for identification of stage. Now, for the establishment of a toxicity screening approach using 5/6 NX rats, our concept, "Differential toxicity synchronized with renal dysfunction process could be identified using 5/6 NX rats" was examined by dosing gentamicin. Firstly, electrophoretic fractional changes of urinary proteins during gentamicin treatment were clarified with determination of amino acid sequences and the three differential features were proven, revealing the unpredictable depression of urinary albumin with progression of the stages in NX rats. Secondly, marked elevation of urinary lactate dehydrogenase (LDH) and glucose (GLU) was evident, indicating the intensified hypoxic conditions and glycolysis in tubular cells synchronized with increased tubular damage. Thirdly, these transit metabolic changes were proven as intensive cause for the advancement of renal dysfunction by the reduction of FRelectrolytes and water at the end of each dosing period. These results indicate that toxicity studies of newly developed drugs using 5/6 NX rats have potentiality prior to clinical dosing to the patients.


Subject(s)
Anti-Bacterial Agents/toxicity , Blood Proteins/metabolism , Drug Evaluation, Preclinical/methods , Gentamicins/toxicity , Kidney/metabolism , Renal Insufficiency , Albumins/metabolism , Amino Acid Sequence , Animals , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/urine , Creatinine/urine , Disease Models, Animal , Electrolytes/metabolism , Gentamicins/blood , Gentamicins/urine , Glycosuria , Kidney/pathology , L-Lactate Dehydrogenase/urine , Male , Nephrectomy , Proteinuria , Rats , Rats, Wistar , Renal Insufficiency/metabolism
3.
J Toxicol Sci ; 23(5): 433-42, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9922947

ABSTRACT

It has been established that progression of renal lesions in 5/6 nephrectomized rats, in which the total right kidney was removed and two poles of the left kidney were excised surgically, and are used as an animal model of renal failure in man, can be morphologically divided into three stages. In the present study, for establishing a renal toxicity study using this animal model on the physiological side, changes of biochemical parameters were sequentially investigated in 20 male 5/6 nephrectomized Wistar rats until 26 weeks after nephrectomy. Creatinine clearance (CLcre) and water as well as electrolyte reabsorption (FRwater and FR Na, K, Cl) were reduced at weeks 2-4, then increased slightly from weeks 6 to 10, and reduced again thereafter. On the contrary, urinary protein was elevated throughout the experimental period, while albumin fraction was increased after week 2 and low-molecular tubular protein increased after week 6 by electrophoresis. Urinary LDH also demonstrated high levels throughout the observation period, but ALP only increased after week 18. The present study thus confirmed that renal function after 5/6 nephrectomy is indeed changed in three stages with clinical biochemical parameters, especially CLcre and FR Na, K, Cl being good indicators to distinguish the three stages of glomerular and tubular dysfunction, respectively. In addition, urinary protein-fractions by electrophoresis in this animal model were examined for the first time, proving useful approach to glomerular and tubular dysfunction.


Subject(s)
Kidney/metabolism , Nephrectomy , Albumins/metabolism , Animals , Creatinine/metabolism , Disease Models, Animal , Electrolytes/metabolism , Glucose/metabolism , Kidney Glomerulus/physiopathology , Kidney Tubules/physiopathology , Male , Rats , Rats, Wistar , Urine , Water/metabolism
4.
Toxicol Pathol ; 24(4): 498-501, 1996.
Article in English | MEDLINE | ID: mdl-8864192

ABSTRACT

A case of superficial necrolytic dermatitis in a young laboratory beagle dog with diabetes mellitus was investigated. Macroscopically, the skin lesion was restricted to paws showing erosion and swelling of the interdigital areas. The most predominant histopathological feature was upper-epidermal vacuolation of keratinocytes. In the pancreas, the number and size of islets were found to be markedly reduced, and only glucagon-positive cells were detected. In the liver, severe and widespread vacuolation of hepatocytes was observed. Blood biochemical assays showed that the serum glucose and plasma glucagon levels were increased. In addition, levels of individual amino acids varied markedly, although the total amino acid concentration was within the normal range. From these results, it was suggested that the skin lesion in this case was primarily caused by hyperglucagonemia in diabetes mellitus.


Subject(s)
Dermatitis/pathology , Diabetes Mellitus, Type 1/veterinary , Dog Diseases/pathology , Amino Acids/blood , Animals , Dermatitis/blood , Dermatitis/etiology , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Dog Diseases/blood , Dogs , Enzymes/blood , Glucagon/metabolism , Keratinocytes/ultrastructure , Leukocyte Count , Liver/pathology , Male , Necrosis , Pancreas/pathology , Periodic Acid-Schiff Reaction
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