Cyclin I protects podocytes from apoptosis
Cyclin I protects podocytes from apoptosis
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DOI：
10.1074/jbc.m513336200
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发表时间：
2006-09-22
影响因子：
4.8
通讯作者：
Shankland, Stuart J.
中科院分区：
文献类型：
--
作者：
Griffin, Sian V.;Olivier, J. Paul;Shankland, Stuart J.
损伤后肾小球足细胞的再生能力有限，是肾小球硬化和进行性肾脏衰竭的发展。我们发现，在肾脏中，细胞周期蛋白I在肾小球足细胞中唯一表达，并且已经构建了细胞周期蛋白I敲除小鼠，以探索细胞周期蛋白I在这些细胞中的生物学功能。 Cyclin I敲除（ - / - ）足细胞在体外和体内都显示出对凋亡的敏感性增加。诱导实验性肾小球肾炎后，在细胞周期蛋白I - / - 小鼠中，足细胞凋亡增加了4倍，这与肾功能急剧降低有关。我们先前的数据表明，CDK抑制剂P21（CIP1/WAF1）保护足细胞免受某些凋亡刺激的影响。在培养的细胞周期蛋白I - / - 足细胞中，基础线的p21（CIP1/WAF1）水平较低，半寿命较短，并且对凋亡刺激的响应速度较快，而不是野生型细胞。 P21（CIP1/WAF1）的强制表达反转了细胞周期蛋白I - / - 足细胞对凋亡的敏感性。 Cyclin I可保护足细胞免受凋亡的影响，我们提供初步数据，以表明这是由P21稳定（CIP1/WAF1）介导的。
The limited regenerative capacity of the glomerular podocyte following injury underlies the development of glomerulosclerosis and progressive renal failure in a diverse range of kidney diseases. We discovered that, in the kidney, cyclin I is uniquely expressed in the glomerular podocyte, and have constructed cyclin I knock-out mice to explore the biological function of cyclin I in these cells. Cyclin I knock-out (-/-) podocytes showed an increased susceptibility to apoptosis both in vitro and in vivo. Following induction of experimental glomerulonephritis, podocyte apoptosis was increased 4-fold in the cyclin I -/- mice, which was associated with dramatically decreased renal function. Our previous data showed that the Cdk inhibitor p21(Cip1/Waf1) protects podocytes from certain apoptotic stimuli. In cultured cyclin I -/- podocytes, the level of p21(Cip1/Waf1) was lower at base line, had a shorter half-life, and declined more rapidly in response to apoptotic stimuli than in wild- type cells. Enforced expression of p21(Cip1/Waf1) reversed the susceptibility of cyclin I -/- podocytes to apoptosis. Cyclin I protects podocytes from apoptosis, and we provide preliminary data to suggest that this is mediated by stabilization of p21(Cip1/Waf1).