Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury

Nat Med. 2010 May;16(5):535-43, 1p following 143. doi: 10.1038/nm.2144. Epub 2010 May 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Adult
  • Cell Cycle*
  • Epithelial Cells / metabolism*
  • Fibrosis
  • Glomerulonephritis / genetics
  • Humans
  • Kidney / metabolism*
  • Kidney / pathology*
  • Kidney Diseases / genetics
  • Kidney Diseases / pathology
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Tumor Suppressor Protein p53
  • Mitogen-Activated Protein Kinase 9