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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-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G-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-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-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G-M arrest is induced in kidney injury and how G-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.
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