Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury
By Tatiana Y. Besschetnova, C. Brooks, Jagesh V. Shah, Joseph V. Bonventre. Nature Medicine, 2010
1,270 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Nephrology
View Paper: https://www.semanticscholar.org/paper/45fa2f4322881ce2ae2b3027e73413519fdb4d1a
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Citations in the corpus
- Cellular and molecular mechanisms of renal fibrosis (2011, background): “Furthermore, defects in progression of the cell cycle after injury, such as arrest at G2/M phase, cause tubular cells to switch to a profibrotic phenotype with an increased expression of TGF-β, thereby promoting fibrosis”
- Epithelial to Mesenchymal Transition induces cell cycle arrest and parenchymal damage in renal fibrosis (2015, neutral): “In particular, while repair of injured TECs involves the proliferation of these cells to repopulate the renal tubules with functional epithelium 25,26 , it remains unclear whether EMT is directly associated with cell cycle arrest of these cells, and whether gain of mesenchymal features by these…”
- Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. (2012, background): “Both studies by Yang et al.(63) and Bechtel et al.”
- Renal tubule injury: a driving force toward chronic kidney disease. (2018, background): “A series of elegant studies found that cell-cycle arrest in TECs is an important driver of maladaptive repair and renal fibrosis.(60,145,210) Yang et al.”
- Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. (2012, background): “This up-regulation is associated with a marked increase in the percentage of cells in the G2/M phase of the cell cycle, which is confirmed in vivo using different acute kidney disease mouse models.(73) The contribution of PTCs is further supported in a tetracyclineinducible transgenic mouse model, i”
- Cellular and molecular mechanisms in kidney fibrosis. (2014, positive): “Stressed epithelium of the nephron signals into the interstitial space, employing factors including PDGFs, activated TGF-β, WNTs, Notch, connective tissue growth factor (CTGF), and Hedgehog ligands (9, 10, 38, 63, 64).”
- Pathophysiology of Acute Kidney Injury (2012, positive): “, in which cells that are growth arrested in G2/M express high levels of profibrotic cytokines such as TGF-beta and CTGF (617).”
- Host Responses in Tissue Repair and Fibrosis (2012, background): “Increasing examples of epithelial stress, including ER stress, dysregulation of energy metabolism, and arrest in G2 of the cell cycle, are sufficient to activate intracellular signaling programs that confer a profibrotic phenotype on the epithelial cell without necessarily activating the development”