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Induction of Cellular DNA Synthesis in the Pancreas and Kidneys of Rats by Peroxisome Proliferators, 9-cis Retinoic Acid, and 3,3',5-Triiodo-L-thyronine¹

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 [T. O., S. L. K., J. L.], and Institute of Experimental Pathology, University of Cagliari, 09124 Cagliari, Italy [G. M. L-C., A. C., H. S.]

We recently suggested that peroxisome proliferators (PPs), 3,3',5-triiodo-L-thyronine (T₃), and 9-cis retinoic acid (9-cis RA) induce hepatocyte proliferation in rats through the activation of their nuclear receptors, PP-activated receptors, T₃ receptors, and retinoid X receptors. To test whether nuclear hormone receptor-mediated cell proliferation can be observed in organs other than liver, we examined the effects of these agents on the pancreas and kidneys of male Wistar rats using BrdUrd immunohistochemistry. A single s.c. injection of T₃ (2 mg/kg) and single intragastric administration of 9-cis RA (40 mg/kg) or 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-ß-hydroxyethyl) acetamide (200 mg/kg) induced a wave of DNA synthesis in the pancreatic acinar cells and in the proximal tubular epithelial cells of the kidneys, peaking after 24 h. No stimulation of DNA synthesis was observed in ductal or islet cells of the pancreas and in glomeruli of the kidneys. All-trans-retinoic acid, a ligand for retinoic acid receptor, at a dose (200 mg/kg) that induced hepatocyte proliferation, had no effects on cell proliferation of the pancreas and the kidneys. The results suggest that T₃, 9-cis RA, and PP activate genes that regulate cell proliferation in target cells through receptor-mediated pathways and initiate cellular DNA synthesis.

¹ The study was supported by Grant CA53453 from NIH, a grant from the Pathology Education and Research Foundation (Pittsburgh, PA), Consiglio Nazionale delle Ricerche (PF ACRO), and the Associazione Italiana Ricerca sul Cancro.

² To whom requests for reprints should be addressed, at Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Phone: (412) 648-9478; Fax: (412) 648-1916; E-mail: shino+@pitt.edu.

Received 11/20/96. Accepted 1/19/97.

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