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Cellular Analysis of Renal Neoplasia: Light Microscope Study of the Development of Interstitial Lesions Induced in the Rat Kidney by a Single Carcinogenic Dose of Dimethylnitrosamine

Medical Research Council Laboratories, Toxicology Research Unit, Woodmansterne Road, Carshalton, Surrey, England

Rats conditioned by a protein-depleted diet were treated with a single i.p. dose of 50 or 60 mg/kg dimethylnitrosamine. Rats fed a casein-supplemented diet were given injections of 30 mg/kg. The sequential changes induced in the kidney were followed by light microscopy, first at daily intervals and then at weekly, biweekly, and monthly intervals from 1 day to 25 weeks, by which time mesenchymal tumor development was obvious. The incidence of early lesions in rats at the three dose levels correlated with the anticipated tumor incidence assessed from simultaneous studies. The characteristic lesion was a hypercellular aggregation within the interstitium in the vicinity of glomeruli. This lesion was first seen at 2 to 4 days and reached its height of development by 7 to 14 days, when there was a tendency to a diffuse increase in cells of the cortical interstitium. There was a progressive decline in these lesions in ensuing weeks, but in rats destined to develop mesenchymal tumor they never altogether disappeared. Up to and including 8 weeks, the interstitial lesions were characterized by inflammatory mononuclear cells, with cells of the immunological series becoming more dominant with time. Coincident with a sudden reduction in numbers of immunological cells, the first aggregates of tumor cells could be recognized at 12 weeks. By 16 weeks, these had assumed unequivocal tumor morphology, although they were still of microscopic proportions. By 20 weeks, the growths were macroscopic, and at 25 weeks they could deform normal kidney shape. The range of alteration of sequestered epithelial components within these tumors is described. There was no evidence of formation of primitive nephrons, although epithelial tumors could occur independently within the mass of a mesenchymal tumor. It is concluded that the dimethylnitrosamine-induced renal mesenchymal tumor originates from cells of the cortical interstitium near the glomerular hilus. It is further concluded that such cells are not capable of bipotential differentiation.

Received 5/18/70. Accepted 7/15/70.