title: Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
abstract: Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.
authors.affiliation: Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Besschetnova
authors.forename: Craig R
authors.initials: CR
authors.lastname: Brooks
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics; D000328:Adult; D002453:Cell Cycle; D004847:Epithelial Cells / Q000378:metabolism*; D005355:Fibrosis; D005921:Glomerulonephritis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D048056:Mitogen-Activated Protein Kinase 9