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

Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV
Nat Med. 2010 16 (5): 535-43, 1p following 143

PMID: 20436483 · PMCID: PMC3928013 · DOI:10.1038/nm.2144

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.

MeSH Terms (11)

Acute Kidney Injury Adult Cell Cycle Epithelial Cells Fibrosis Glomerulonephritis Humans Kidney Kidney Diseases Mitogen-Activated Protein Kinase 9 Tumor Suppressor Protein p53

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