期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 11, 期 476, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aav4754
关键词
-
资金
- Safra Foundation
- NIH [R37DK039773, R01DKD072381, K01DK099473, P30 DK114809]
- Philippe Foundation Inc.
- Bettencourt Schueller Foundation
- Societe Francaise de Nephrologie
- Emmanuel Boussard Foundation (London, UK)
- Day Solvay Foundation (Paris, France)
- Assistance Publique-Hopitaux de Paris
- University Paris Descartes
- Sumitomo Life Welfare and Culture Foundation, Japan
- [16 K09620]
Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G(2)-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G(2)-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G(2)-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G(2)-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G(2)-M arrest is induced in kidney injury and how G(2)-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据