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Toxicologic Pathology
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Articles

Nephrotic Syndrome Induced by Dibasic Sodium Phosphate Injections for Twenty-eight Days in Rats

Noriko Tsuchiya1, Mikinori Torii1, Isao Narama2 and Takane Matsui3

1 Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan
2 Department of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, Japan
3 Department of Pathological Science, Obihiro University of Agriculture and Veterinary Medicine, Japan

Correspondence: Noriko Tsuchiya, DVM, Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1Futaba-cho, Toyonaka, Osaka 561-0825, Japan; e-mail:noriko.tsuchiya{at}shionogi.co.jp.

Sprague-Dawley rats received once daily tail-vein injections of 360 mM dibasic sodium phosphate solution at 8 mL/kg for fourteen or twenty-eight days. Clinical examination revealed persistent proteinuria from three days after the first dosing and thereafter severe proteinuria from eight days or later in the phosphate-treated groups. Proteinuria developed without remission even after fourteen-day withdrawal in the fourteen-day dosed group. Phosphate-treated animals developed lipemia, hypercholesterolemia, anemia, higher serum fibrinogen levels, and lower serum albumin/globulin ratios on day 29. Renal weight increased significantly compared with control animals, and the kidneys appeared pale and enlarged with a rough surface. Histopathologically, glomerular changes consisted of mineralization in whole glomeruli, glomerular capillary dilatation, partial adhesion of glomerular tufts to Bowman’s capsule, and mesangiolysis. Ultrastructural lesions such as an increased number of microvilli, effacement of foot processes, and thickening of the glomerular basement membrane, and immunocytochemical changes in podocytes, mainly decreased podoplanin-positive cells and increased desmin expression, were also conspicuous in the phosphate-treated rats for twenty-eight days. Marked tubulointerstitial lesions were tubular regeneration and dilatation, protein casts, mineralization in the basement membrane, focal interstitial inflammation, and fibrosis in the cortex. These clinical and morphological changes were similar to features of human nephrotic syndrome.

Key Words: rat • nephrotic syndrome • animal model • glomerulus • calcification • electron microscopy • Na2HPO4

This version was published on April 1, 2009

Toxicologic Pathology, Vol. 37, No. 3, 270-279 (2009)
DOI: 10.1177/0192623309332996
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