Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
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纤维化是导致慢性进行性肾衰竭的原因，其存在于发达国家的大量成年人中。越来越多的人认识到，导致异常不完全修复的急性肾损伤（阿基）是慢性纤维化肾病的主要原因。损伤后引发纤维化反应的机制尚不清楚。在阿基的缺血性、毒性和阻塞性模型中，我们证明了上皮细胞周期G2/M阻滞与纤维化结局之间的因果关系。G2/M期阻滞的近端肾小管细胞激活c-jun NH 2-末端激酶（JNK）信号传导，其作用是上调促纤维化细胞因子的产生。用JNK抑制剂治疗，或通过给予p53抑制剂绕过G2/M期阻滞或切除对侧肾脏，挽救单侧缺血性损伤肾脏中的纤维化。因此，上皮细胞周期停滞在G2/M及其随后的下游信号传导是迄今为止尚未认识到的用于预防纤维化和中断肾脏疾病加速进展的治疗靶点。
Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH2-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.
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DOI：
10.1097/01.asn.0000067652.51441.21
发表时间：
2003-06-01
影响因子：
13.6
作者：
Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
13.6
作者：
Ishani, Areef;Xue, Jay L.;Collins, Allan J.
通讯作者：
Collins, Allan J.
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
5.6
作者：
Ikawa, Yuka;Ng, Poh-Sing;Takehara, Kazuhiko
通讯作者：
Takehara, Kazuhiko
影响因子：
19.6
作者：
Lameire, N;Jager, K;Vanholder, R
通讯作者：
Vanholder, R