| First Author | Canaud G | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 476 | PubMed ID | 30674655 |
| Mgi Jnum | J:273035 | Mgi Id | MGI:6275673 |
| Doi | 10.1126/scitranslmed.aav4754 | Citation | Canaud G, et al. (2019) Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair. Sci Transl Med 11(476) |
| abstractText | 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. |
