Published online before print July 9, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070279

Accepted for publication May 9, 2007.

Article

Renal Damage in Obstructive Nephropathy Is Decreased in Skp2-Deficient Mice

Sayuri Suzuki^*, Hirotaka Fukasawa, Kyoko Kitagawa^*, Chiharu Uchida^*, Takayuki Hattori^*, Tomoyasu Isobe^*, Toshiaki Oda^*, Taro Misaki^*, Naro Ohashi, Keiko Nakayama, Keiichi I. Nakayama, Akira Hishida, Tatsuo Yamamoto, and Masatoshi Kitagawa^*@

From the Department of Biochemistry 1* and the First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu; the Division of Developmental Genetics, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, Miyagi; and the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

^@ To whom correspondence should be addressed. E-mail: kitamasa{at}hama-med.ac.jp.

	Abstract

Ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27 mediated by SCF-Skp2 ubiquitin ligase is involved in cell cycle regulation. Proliferation of tubular cells is a characteristic feature in obstructed kidneys of unilateral ureteral obstruction. Comparing Skp2^+/+ mice with Skp2^-/- mice, we investigated the involvement of Skp2, a component of SCF-Skp2 ubiquitin ligase for p27, in the progression of renal lesions in unilateral ureteral obstructed kidneys. mRNA expression of Skp2 was markedly increased in the obstructed kidneys from Skp2^+/+ mice and peaked 3 days after unilateral ureteral obstruction. Renal atrophy, tubular dilatation, tubulointerstitial fibrosis, and increases in -smooth muscle actin expression, the number of tubular cells, and proliferating tubular cells positive for Ki67 were observed in the obstructed kidneys from Skp2^+/+ mice; however, these findings were significantly attenuated in Skp2^-/- mice. The p27 protein level was increased in the obstructed kidneys but was significantly greater in Skp2^-/- mice. The number of Ki67-positive p27-negative cells was lower in obstructed kidneys from Skp2^-/- mice than Skp2^+/+ mice, whereas that of Ki67-negative p27-positive cells was greater in Skp2^-/- mice. These findings suggest that p27 accumulation, which results from SCF-Skp2 ubiquitin ligase deficiency in Skp2^-/- mice, is involved in the amelioration of renal damage induced by obstructive nephropathy.

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