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Sci Transl Med. 2019 Jan 23;11(476). pii: eaav4754. doi: 10.1126/scitranslmed.aav4754.

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

Author information

1
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
INSERM U1151, Institut Necker-Enfants Malades, Université Paris Descartes, Paris 75743, France.
3
Service de Néphrologie et Transplantation Adultes, Hôpital Necker-Enfants Malades, Paris 75743, France.
4
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
5
Department of Nephrology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 7708503, Japan.
6
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Renal Division, Peking University First Hospital, Beijing 100871, China.
8
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. joseph_bonventre@hms.harvard.edu.
9
Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
10
Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

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.

PMID:
30674655
PMCID:
PMC6527117
[Available on 2020-01-23]
DOI:
10.1126/scitranslmed.aav4754

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