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Toxicologic Pathology
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Glomerulonephritis with Fibrillary Deposition in a Transgenic Mouse Carrying the Human Prototype c-Ha-ras Gene (rasH2 Mouse)

Kiyoshi Kobayashi

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Yokohama 227-0033, Japan, 1703523@ mitsubishi-pharm.co.jp

Fumiko Sano

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Yokohama 227-0033, Japan

Mamoru Mutai

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Yokohama 227-0033, Japan

Jiro Sugimoto

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Yokohama 227-0033, Japan

Glomerulonephritis was observed in a 34-week-old transgenic CB6F1 mouse carrying the human prototype c-Ha-ras gene (rasH2 mouse) from a medium-term carcinogenicity study of N-methyl-N-nitrosourea (MNU). Lesions were characterized by severe diffuse enlargement and prominent hyalinization of glomeruli. The hyaline material was positive for periodic acid-Schiff but negative for amyloid by the Congo red method. Immunohistochemically, affected glomeruli were positive for polyclonal anti-mouse IgG. Ultra-structurally, there were characteristic subendothelial and mesangial deposits composed of fibrils showing a fingerprint pattern. Lamellae were 7.5-14.3 nm in diameter and formed multilayered structures. In addition to the renal lesions, a lymphoma was observed in the thymus, with metastasis to the spleen and some lymph nodes. However, there was no glomerulonephritis in 32 other mice bearing thymic lymphomas and in more than 40 males and females given MNU in the same study. Thus, the lesions in this mouse may have been spontaneous. Glomerulonephritis was not found in more than 120 other male and female rasH2 mice in our facility. This is the first report of glomerulonephritis in a rasH2 mouse, a promising candidate for medium-term carcinogenicity risk assessment.

Key Words: Glomerulonephritis • rasH2 mouse • fibril deposition

Toxicologic Pathology, Vol. 28, No. 2, 359-362 (2000)
DOI: 10.1177/019262330002800217
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 Toxicol PatholHome page
T. Usui, M. Mutai, S. Hisada, M. Takoaka, K. A. Soper, B. Mccullough, and C. Alden
CB6F1-rasH2 Mouse: Overview of Available Data
Toxicol Pathol, January 1, 2001; 29(1_suppl): 90 - 108.
[Abstract] [PDF]