Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice
Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice
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DOI：
10.2353/ajpath.2007.070279
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发表时间：
2007-08-01
影响因子：
6
通讯作者：
Kitagawa, Masatoshi
中科院分区：
文献类型：
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作者：
Suzuki, Sayuri;Fukasawa, Hirotaka;Kitagawa, Masatoshi
由SCF-Skp 2泛素连接酶介导的细胞周期蛋白依赖性激酶抑制剂p27的泛素依赖性降解参与细胞周期调节。肾小管上皮细胞增生是单侧输尿管梗阻的特征性表现。比较Skp 2（+/+）小鼠和Skp 2（-/-）小鼠，我们研究了Skp 2（SCF-Skp 2泛素连接酶p27的一个组分）在单侧输尿管梗阻肾脏病变进展中的参与。Skp 2（+/+）小鼠梗阻肾脏中Skp 2 mRNA表达明显增加，并在单侧输尿管梗阻后3天达到峰值。在Skp 2（+/+）小鼠的阻塞肾脏中观察到肾萎缩、肾小管扩张、肾小管间质纤维化和α-平滑肌肌动蛋白表达、肾小管细胞数量和Ki 67阳性的增殖肾小管细胞增加;然而，这些发现在Skp 2（-/-）小鼠中显著减弱。阻塞肾脏中的p27蛋白水平增加，但Skp 2（-/-）小鼠中的p27蛋白水平显着更高。Skp 2（-/-）小鼠梗阻肾中Ki 67阳性p27阴性细胞的数量低于Skp 2（+/+）小鼠，而Skp 2（-/-）小鼠中Ki 67阴性p27阳性细胞的数量高于Skp 2（+/+）小鼠。这些发现表明，在Skp 2（-/-）小鼠中，由SCF Skp 2泛素连接酶缺陷引起的p27积累参与了阻塞性肾病诱导的肾损伤的改善。
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 a-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.