Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice.
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 alpha-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.
Suzuki
Sayuri
S
Department of Biochemistry 1, Hamamatsu University School of Medicine, Japan.
Fukasawa
Hirotaka
H
Kitagawa
Kyoko
K
Uchida
Chiharu
C
Hattori
Takayuki
T
Isobe
Tomoyasu
T
Oda
Toshiaki
T
Misaki
Taro
T
Ohashi
Naro
N
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Hishida
Akira
A
Yamamoto
Tatsuo
T
Kitagawa
Masatoshi
M
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D005838:Genotype; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism
D019394:Ki-67 Antigen; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044843:SKP Cullin F-Box Protein Ligases