Cyclin G1 and TASCC regulate kidney epithelial cell G 2 -M arrest and fibrotic maladaptive repair
| Autor: | Adam Scott, Sato Magassa, Kenji Nishimura, Guillaume Canaud, Takaharu Ichimura, Kensei Taguchi, Craig R. Brooks, Li Yang, Fabiola Terzi, Li-Li Hsiao, Seiji Kishi, Joseph V. Bonventre |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Kidney Cell cycle checkpoint endocrine system diseases business.industry Autophagy 030232 urology & nephrology Acute kidney injury General Medicine medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Fibrosis Cancer research Medicine Secretion business Cyclin Kidney disease |
| Zdroj: | Science Translational Medicine. 11 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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 G2-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G2-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 G2-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 G2-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G2-M arrest is induced in kidney injury and how G2-M–arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis. |
| Databáze: | OpenAIRE |
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