This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schaffner, D. L. Articles by Lieberman, M. W. Search for Related Content PubMed PubMed Citation Articles by Schaffner, D. L. Articles by Lieberman, M. W.

American Journal of Pathology, Vol 142, 1051-1060, Copyright © 1993 by American Society for Investigative Pathology

REGULAR ARTICLES

Targeting of the rasT24 oncogene to the proximal convoluted tubules in transgenic mice results in hyperplasia and polycystic kidneys

DL Schaffner, R Barrios, C Massey, EI Banez, CN Ou, S Rajagopalan, E Aguilar- Cordova, RM Lebovitz, PA Overbeek and MW Lieberman
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030.

Five families of transgenic mice were derived from one-cell-stage embryos injected with gamma GT-rasT24, a fusion gene consisting of the gamma-glutamyl transpeptidase (gamma GT) 5' flanking region containing promoter I linked to a mutated (codon 12) human H-ras oncogene. The transgene was expressed selectively in the kidneys, eyes, and brains of all families as determined by reverse transcription-polymerase chain reaction, nuclease protection assays, and in situ hybridization. In two of five families, kidney lesions consisting of proximal tubular hyperplasia, renal cysts, and microadenomas developed in male animals; males also expressed higher levels of gamma GT/rasT24 RNA. Early lesions consisted of proximal tubular hyperplasia as defined by alkaline phosphatase histochemistry, gamma GT immunohistochemistry, and electron microscopy and could be correlated with the presence of rasT24 RNA within the cystic proximal tubular epithelium by in situ hybridization. Advanced lesions also involved other segments of the nephron and consisted of cysts lined by a flattened unicellular layer of attenuated epithelium. No rasT24 could be identified within cystic lesions of the distal nephron and collecting tubules by in situ hybridization, and they most likely arise by external compression. Animals from the two transgenic strains exhibiting cystic lesions die of renal failure beginning at 8 months of age. No difference in cell- cycle parameters or DNA ploidy between transgenic and control kidneys was identified by flow cytometric analysis. No renal carcinomas developed. The primary renal effects of the H-rasT24 oncogene in this model system consist of proximal tubular hyperplasia 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.

This article has been cited by other articles:

				S. Cheng, A. S. Pollock, R. Mahimkar, J. L. Olson, and D. H. Lovett Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury FASEB J, September 1, 2006; 20(11): 1898 - 1900. [Abstract] [Full Text] [PDF]

				K. E. Bernstein, H. D. Xiao, J. W. Adams, K. Frenzel, P. Li, X. Z. Shen, J. M. Cole, and S. Fuchs Establishing the Role of Angiotensin-Converting Enzyme in Renal Function and Blood Pressure Control through the Analysis of Genetically Modified Mice J. Am. Soc. Nephrol., March 1, 2005; 16(3): 583 - 591. [Full Text] [PDF]

				Y. Tao, J. Kim, R. W. Schrier, and C. L. Edelstein Rapamycin Markedly Slows Disease Progression in a Rat Model of Polycystic Kidney Disease J. Am. Soc. Nephrol., January 1, 2005; 16(1): 46 - 51. [Abstract] [Full Text] [PDF]

				T. H. Le, M. I. Oliverio, H.-S. Kim, H. Salzler, R. C. Dash, D. N. Howell, O. Smithies, S. Bronson, and T. M. Coffman A {gamma}GT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice Physiol Genomics, August 11, 2004; 18(3): 290 - 298. [Abstract] [Full Text] [PDF]

				P. D. Wilson Polycystic Kidney Disease N. Engl. J. Med., January 8, 2004; 350(2): 151 - 164. [Full Text] [PDF]

				N. M. Fiaschi-Taesch, S. Santos, V. Reddy, S. K. Van Why, W. F. Philbrick, A. Ortega, P. Esbrit, J. J. Orloff, and A. Garcia-Ocana Prevention of Acute Ischemic Renal Failure by Targeted Delivery of Growth Factors to the Proximal Tubule in Transgenic Mice: The Efficacy of Parathyroid Hormone-Related Protein and Hepatocyte Growth Factor J. Am. Soc. Nephrol., January 1, 2004; 15(1): 112 - 125. [Abstract] [Full Text] [PDF]

				S. Zhao, F.-C. Hung, J. S. Colvin, A. White, W. Dai, F. J. Lovicu, D. M. Ornitz, and P. A. Overbeek Patterning the optic neuroepithelium by FGF signaling and Ras activation Development, December 15, 2001; 128(24): 5051 - 5060. [Abstract] [Full Text] [PDF]

				L. Pritchard, J. A. Sloane-Stanley, J. A. Sharpe, R. Aspinwall, W. Lu, V. Buckle, L. Strmecki, D. Walker, C. J. Ward, C. E. Alpers, et al. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype Hum. Mol. Genet., November 1, 2000; 9(18): 2617 - 2627. [Abstract] [Full Text] [PDF]

				F. TERZI, M. BURTIN, and G. FRIEDLANDER Using Transgenic Mice to Analyze the Mechanisms of Progression of Chronic Renal Failure J. Am. Soc. Nephrol., November 1, 2000; 11(90002): 144S - 148. [Abstract] [Full Text]

				C. A. Omer, Z. Chen, R. E. Diehl, M. W. Conner, H. Y. Chen, M. E. Trumbauer, S. Gopal-Truter, G. Seeburger, H. Bhimnathwala, M. T. Abrams, et al. Mouse Mammary Tumor Virus-Ki-rasB Transgenic Mice Develop Mammary Carcinomas That Can Be Growth-inhibited by a Farnesyl:Protein Transferase Inhibitor Cancer Res., May 1, 2000; 60(10): 2680 - 2688. [Abstract] [Full Text]

				L. M. Guay-Woodford, W. J. Green, J. R. Lindsey, and D. R. Beier Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated Hum. Mol. Genet., March 22, 2000; 9(5): 769 - 778. [Abstract] [Full Text] [PDF]

				P. K. Stricklett, R. D. Nelson, and D. E. Kohan The Cre/loxP system and gene targeting in the kidney Am J Physiol Renal Physiol, May 1, 1999; 276(5): F651 - F657. [Abstract] [Full Text] [PDF]

				M. P. Emert, C. M. Sorenson, D. P. Basile, J. G. Rogers, M. R. Hammerman, and J. J. Billadello The human plasminogen activator inhibitor type I gene promoter targets to kidney Am J Physiol Renal Physiol, February 1, 1998; 274(2): F405 - F412. [Abstract] [Full Text] [PDF]

				L. Tsiokas, E. Kim, T. Arnould, V. P. Sukhatme, and G. Walz Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2 PNAS, June 24, 1997; 94(13): 6965 - 6970. [Abstract] [Full Text] [PDF]

				A. R. Sepulveda, S. L. Huang, R. M. Lebovitz, and M. W. Lieberman A 346-Base Pair Region of the Mouse gamma -Glutamyl Transpeptidase Type II Promoter Contains Sufficient Cis-acting Elements for Kidney-restricted Expression in Transgenic Mice J. Biol. Chem., May 2, 1997; 272(18): 11959 - 11967. [Abstract] [Full Text] [PDF]

				G. M. Habib, R. Barrios, Z.-Z. Shi, and M. W. Lieberman Four Distinct Membrane-bound Dipeptidase RNAs Are Differentially Expressed and Show Discordant Regulation with gamma -Glutamyl Transpeptidase J. Biol. Chem., July 5, 1996; 271(27): 16273 - 16280. [Abstract] [Full Text] [PDF]

				G. M. Habib, B. Z. Carter, A. R. Sepulveda, Z.-Z. Shi, D.-F. Wan, R. M. Lebovitz, and M. W. Lieberman Identification of a Sixth Promoter That Directs the Transcription of [IMAGE]-Glutamyl Transpeptidase Type III RNA in Mouse J. Biol. Chem., June 9, 1995; 270(23): 13711 - 13715. [Abstract] [Full Text] [PDF]