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

Ubiquitin-dependent degradation of the cyclin-dependent kinaseinhibitor p27 mediated by SCF-Skp2 ubiquitin ligase is involvedin cell cycle regulation. Proliferation of tubular cells isa characteristic feature in obstructed kidneys of unilateralureteral obstruction. Comparing Skp2^+/+ mice with Skp2^–/–mice, we investigated the involvement of Skp2, a component ofSCF-Skp2 ubiquitin ligase for p27, in the progression of renallesions in unilateral ureteral obstructed kidneys. mRNA expressionof Skp2 was markedly increased in the obstructed kidneys fromSkp2^+/+ mice and peaked 3 days after unilateral ureteral obstruction.Renal atrophy, tubular dilatation, tubulointerstitial fibrosis,and increases in ${alpha}$ -smooth muscle actin expression, the numberof tubular cells, and proliferating tubular cells positive forKi67 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 obstructedkidneys but was significantly greater in Skp2^–/–mice. The number of Ki67-positive p27-negative cells was lowerin obstructed kidneys from Skp2^–/– mice than Skp2^+/+mice, whereas that of Ki67-negative p27-positive cells was greaterin Skp2^–/– mice. These findings suggest that p27accumulation, which results from SCF-Skp2 ubiquitin ligase deficiencyin Skp2^–/– mice, is involved in the ameliorationof renal damage induced by obstructive nephropathy.