Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury

被引：1094
作者：
Yang, Li [1 ,2 ]
Besschetnova, Tatiana Y. [1 ,3 ]
Brooks, Craig R. [1 ]
Shah, Jagesh V. [1 ,3 ,4 ]
Bonventre, Joseph V. [1 ,4 ]
机构：
[1] Harvard Univ, Brigham & Womens Hosp, Div Renal, Sch Med,Dept Med, Boston, MA 02115 USA
[2] Peking Univ, Hosp 1, Div Renal, Dept Med, Beijing 100871, Peoples R China
[3] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA
[4] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA USA
来源：
NATURE MEDICINE | 2010年 / 16卷 / 05期
基金：
美国国家卫生研究院;
关键词：
TISSUE-GROWTH-FACTOR; MESENCHYMAL TRANSITION; HISTONE H3; P53; REPAIR; PHOSPHORYLATION; PROLIFERATION; EXPRESSION; MOLECULE-1; MECHANISM;
D O I：
10.1038/nm.2144
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
引用
收藏
页码：535 / U27
页数：10
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