The intranephronal distribution pattern of the activity of succinate dehydrogenase, a marker enzyme of mitochondrial inner membranes, was examined by histochemical investigation in the kidneys of 27 male Sprague-Dawley rats. The animals received cyclosporine A per os (15, 30 or 50 mg/kg.day) for 12 or 24 days. Six animals of the latter group remained untreated for a further 24 days. Five rats treated orally with 30 mg/kg.day olive oil served as controls. The kidneys of 2 normal male Sprague-Dawley rats were examined for comparison. Cyclosporine A reversibly induced a characteristic pattern of nephron segments with various degrees of reduced succinate dehydrogenase activity: in the proximal and distal tubules of subcapsular areas of the cortical labyrinth, of the medullary rays, and of the outer stripe of the outer medulla. The remaining areas contained tubules with normal succinate dehydrogenase activity, as confirmed by microphotometrical measurement. The number of these tubules appeared to be decreased under higher doses of cyclosporine A, irrespective of the duration of treatment. The finding of heterogeneous affection of tubular mitochondrial cristae membranes reflects direct tubulotoxicity of cyclosporine A.

Animals↗

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Nephrotoxicity of cyclosporine A in the rat. II. Reversible changes in intranephronal and urinary catalytic activities of N-acetyl-beta-D-glucosaminidase.

Cyclosporine A (15, 30 or 50 mg/kg.day) or olive oil (30 mg/kg.day) were administered orally to 32 male Sprague-Dawley rats for 12 or 24 days, or withdrawn for 24 days following 24 days of treatment. The specific activity of a lysosomal marker enzyme, N-acetyl-beta-D-glucosaminidase, was determined fluorometrically in single nephron segments microdissected from lyophilized kidney sections of these animals and of an additional 2 normal rats. The segments were classified according to their normal or reduced succinate dehydrogenase activity as detected in stained adjacent sections. In addition, urine specimens collected after 12, 24, 36, and 48 days of the experiment were tested for N-acetyl-beta-D-glucosaminidase activity. After treatment with cyclosporine A, changes in the activities of N-acetyl-beta-D-glucosaminidase were found only in the proximal tubules. In the convoluted segments with normal succinate dehydrogenase activity, the activity of N-acetyl-beta-D-glucosaminidase was 138-163%, and in those with reduced succinate dehydrogenase activity, it was unchanged or 66-83% of the control values. In the straight segments with reduced succinate dehydrogenase activity, the activity of N-acetyl-beta-D-glucosaminidase increased gradually along the medullary rays (122-214%) to the outer stripe of the outer medulla (178-263%) in comparison to the control values. In the urine specimens, the activity of N-acetyl-beta-D-glucosaminidase was increased to 148-152%. These tubular and urinary changes were similar for each dosage and treatment period. After withdrawal of cyclosporine A they were not present. The variety of alterations occurring within the lysosomes along the proximal tubules of cyclosporine-A-treated rats implies the convoluted part as the site of increased release of N-acetyl-beta-D-glucosaminidase into the urine.

Acetylglucosaminidase↗