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, Masatoshi Kitagawa

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18 Citations (Scopus)

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 α-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.

Original languageEnglish
Pages (from-to)473-483
Number of pages11
JournalAmerican Journal of Pathology
Volume171
Issue number2
DOIs
Publication statusPublished - Aug 2007

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K. I., Hishida, A., Yamamoto, T., & Kitagawa, M. (2007). Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. American Journal of Pathology, 171(2), 473-483. https://doi.org/10.2353/ajpath.2007.070279