Study of the Long-Evans Cinnamon (LEC) rat for a model of human renal carcinogenesis

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1. The role of copper and iron on the development of spontaneous renal cell tumors in Long-Evans Cinnamon (LEC) rats was investigated. Copper content in the kidneys of LEC rats in weeks 16-20 when necrotizing hepatitis occurred was 24 times higher than that in F344 rats. Then copper content decreased until 40 weeks, but it was always higher than that in F344 rats. Iron content in the kidney of LEC rats also peaked in weeks 16-20, but it was lower than that in F344 rats after 62 weeks old. Copper staining of the kidney in LEC rats showed positive staining in proximal tubules of the cortex and the outer stripe of the medulla. Long-term treatment of LEC rats with D-penicillamine, a copper-chelating agent, inhibited the development of karyomegaly and BrdU-positive dysplastic tubules. These results suggest that the copper-mediated oxidative DNA damage play an important role in the development of the spontaneous renal cell tumors in LEC rats.2. The role of VHL and Tsc2 genes on the development of renal cell tumors in LEC and F344 rats was investigated by PCR-SSCP.We could not find any mutation in VHL gene. However, we found the Tsc2 gene mutation in the renal cell tumors induced by DEN and EHEN,but not in spontaneous tumors. Loss of heterozygousity on chromosome 10 was found in one of eight (F344xLEC) F1 rats.