Cyclin G1 and TASCC regulate kidney epithelial cell G₂-M arrest and fibrotic maladaptive repair.

Abstract

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.