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Differential toxicity expression of gentamicin in five-sixths nephrectomized rats assigned to three progressive stages of renal dysfunction — establishment of a new screening approach

The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-0000, Japan; 147-6 Kamitamari, Tamari-mura, Niiharigun, Ibaraki 311-3436, Japan; Kyowa Hakko Kogyo, 6-1, Ohthemachi, 1-Chome, Chiyoda-ku, Tokyo 100-8185, Japan

M Yoshida

Department of Pathology, Sasaki Institute, 2-2 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan

R Hokao

S Imai

Imamichi Institute for Animal Reproduction, Ibaraki, Japan

S Takahashi

faculty of Agriculture Yamaguchi University, Yamaguchi, Japan

E Harada

faculty of Agriculture Tottori University, Tottori, Japan

A Maekawa

Department of Pathology, Sasaki Institute, 2-2 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan

Progressive renal dysfunction in 5/6 nephrectomized (NX) rats can be physiologically divided into three stages, coinciding with morphological stages, after definition of physiological parameters for identification of stage. Now, for the establishment of a toxicity screening approach using 5/6 NX rats, our concept, "Differential toxicity synchronized with renal dysfunction process could be identified using 5/6 NX rats" was examined by dosing gentamicin. Firstly, electrophoretic fractional changes of urinary proteins during gentamicin treatment were clarified with determination of amino acid sequences and the three differential features were proven, revealing the unpredictable depression of urinary albumin with progression of the stages in NX rats. Secondly, marked elevation of urinary lactate dehydrogenase (LDH) and glucose (GLU) was evident, indicating the intensified hypoxic conditions and glycolysis in tubular cells synchronized with increased tubular damage. Thirdly, these transit metabolic changes were proven as intensive cause for the advancement of renal dysfunction by the reduction of FR_{electrolytes and water} at the end of each dosing period. These results indicate that toxicity studies of newly developed drugs using 5/6 NX rats have potentiality prior to clinical dosing to the patients.

Key Words: nephrectomy • electrophoresis • albumin • gentamicin • LDH • amino acid sequence

Human & Experimental Toxicology, Vol. 20, No. 2, 100-110 (2001)
DOI: 10.1191/096032701666840048


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