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Autoradiographic Analysis of Proliferative Activity in Rat Kidney Epithelial and Mesenchymal Cell Subpopulations following a Carcinogenic Dose of Dimethylnitrosamine¹

Baker Medical Research Institute, Commercial Road, Prahran, Victoria, 3181 Australia

In a system that yields 100% incidence of renal mesenchymal tumors and a 30 to 40% incidence of renal cortical epithelial neoplasms, the proliferative activity of renal epithelial and mesenchymal cell subpopulations following a single dose of dimethylnitrosamine (DMN) was traced by autoradiographic analysis of [methyl-³H]thymidine uptake during the 3 weeks immediately posttreatment. The initial response to DMN was a depression in DNA synthesis and mitosis to near 0 levels in all segments of the nephron and in attendant mesenchymal cells for a period of 1 to 3 days. Following the period of inhibition, increased DNA synthetic activity was observed in certain subpopulations of both epithelium and mesenchyme and these patterns were matched by equivalent mitotic activity. A stimulation of DNA synthesis was observed in cells of the proximal and distal tubules of Zones 1 and 2 but in no other epithelial segments. The increased activity was most intense in Zone 1 epithelium reaching a peak at the 10th day after DMN injection, 4 days after epithelial cell necrosis had commenced.

In renal mesenchyme, the major response involved only the interstitial cells of Zones 1 and 2. At Day 3, there was a wave of increased DNA-synthetic and mitotic activity in the free interstitial cells of the cortex, followed by a 2nd, more intense peak of activity at Day 6. The cells responding at Day 3 appeared to involve the resident population of cortical fibrocytes while the major contribution to the Day 6 peak came from infiltrating mononuclear inflammatory cells, although resident fibrocytes and capillary endothelium also contributed. A significant wave of increased activity involved the interstitial cells of Zone 2, but the peak, although of equivalent intensity to the response in Zone 1, was single and occurred 3 days later at Day 9. Apart from a small, brief, and variable wave of activity in interstitial cells of Zone 3 from Days 8 to 10, no other mesenchymal cell populations in the kidney were stimulated by the injection of DMN.

The carcinogen therefore exerted its most significant effect on those epithelial and mesenchymal cell subpopulations from which the respective neoplasms are believed to be derived.

¹ This work was supported by the A. A. Thomas Research Fellowship of the Anti-Cancer Council of Victoria.

² Arthur A. Thomas Fellow.

Received 6/ 6/75. Accepted 9/ 2/75.