Griffin Siân V, Olivier J Paul, Pippin Jeffrey W, Roberts James M, Shankland Stuart J
Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, 98195, USA.
J Biol Chem. 2006 Sep 22;281(38):28048-57. doi: 10.1074/jbc.M513336200. Epub 2006 Jul 17.
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).
肾小球足细胞损伤后再生能力有限，这是多种肾脏疾病中肾小球硬化和进行性肾衰竭发展的基础。我们发现，在肾脏中，细胞周期蛋白I仅在肾小球足细胞中表达，并构建了细胞周期蛋白I基因敲除小鼠，以探索细胞周期蛋白I在这些细胞中的生物学功能。细胞周期蛋白I基因敲除（-/-）的足细胞在体外和体内对凋亡的敏感性均增加。在诱导实验性肾小球肾炎后，细胞周期蛋白I -/-小鼠的足细胞凋亡增加了4倍，这与肾功能急剧下降有关。我们之前的数据表明，细胞周期蛋白依赖性激酶抑制剂p21（Cip1 / Waf1）可保护足细胞免受某些凋亡刺激。在培养的细胞周期蛋白I -/-足细胞中，p21（Cip1 / Waf1）的水平在基线时较低，半衰期较短，并且与野生型细胞相比，对凋亡刺激的反应下降更快。p21（Cip1 / Waf1）的强制表达逆转了细胞周期蛋白I -/-足细胞对凋亡的敏感性。细胞周期蛋白I保护足细胞免于凋亡，并且我们提供的初步数据表明这是由p21（Cip1 / Waf1）的稳定介导的。
