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

Abstract

Inappropriate wound healing can lead to fibrosis of an organ and interference with its proper function. Joseph Bonventre and his colleagues have found that G2/M cell cycle arrest of tubular epithelial cells in the kidney after acute injury leads to fibrosis and that targeting this arrest, or the signaling that results from this arrest, is ameliorative for disease progression ( pages 523–525 and 544–550 ). 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 NH2-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.