Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury
- PMID: 20436483
- PMCID: PMC3928013
- DOI: 10.1038/nm.2144
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.
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Comment in
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Fibrosis under arrest.Nat Med. 2010 May;16(5):523-5. doi: 10.1038/nm0510-523. Nat Med. 2010. PMID: 20448575 Free PMC article.
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