TARGETING OF THE RAST24 ONCOGENE TO THE PROXIMAL CONVOLUTED TUBULES IN TRANSGENIC MICE RESULTS IN HYPERPLASIA AND POLYCYSTIC KIDNEYS

Five families of transgenic mice were derived from one-cell-stage embr yos injected with gammaGT-rasT24, a fusion gene consisting of the gamm a-glutamyl transpeptidase (gammaGT) 5' flanking region containing prom oter I linked to a mutated (codon 12) human H-ras oncogene. The transg ene was expressed selectively in the kidneys, eyes, and brains of all families as determined by reverse transcription-polymerase chain react ion, nuclease protection assays, and in situ hybridization. In two of five families, kidney lesions consisting of proximal tubular hyperplas ia, renal cysts, and microadenomas developed in male animals; males al so expressed higher levels of gammaGT/rasT24 RNA. Early lesions consis ted of proximal tubular hyperplasia as defined by alkaline phosphatase histochemistry, gammaGT immunohistochemistry, and electron microscopy and could be correlated with the presence of rasT24 RNA within the cy stic proximal tubular epithelium by in situ hybridization. Advanced le sions also involved other segments of the nephron and consisted of cys ts lined by a flattened unicellular layer of attenuated epithelium. No rasT24 could be identified within cystic lesions of the distal nephro n and collecting tubules by in situ hybridization, and they most likel y arise by external compression. Animals from the two transgenic strai ns exhibiting cystic lesions die of renal failure beginning at 8 month s of age. No difference in cell-cycle parameters or DNA ploidy between transgenic and control kidneys was identified by flow cytometric anal ysis. No renal carcinomas developed The primary renal effects of the H -rasT24 oncogene in this model system consist of proximal tubular hype rplasia and polycystic kidneys. This model appears to provide a useful in vivo system for the study of ras oncogene function and control of renal cell proliferation.