| Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. | |
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MedLine Citation:
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PMID: 20436483 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Li Yang; Tatiana Y Besschetnova; Craig R Brooks; Jagesh V Shah; Joseph V Bonventre |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-05-02 |
Journal Detail:
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Title: Nature medicine Volume: 16 ISSN: 1546-170X ISO Abbreviation: Nat. Med. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-07 Completed Date: 2010-07-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: United States |
Other Details:
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Languages: eng Pagination: 535-43, 1p following 143 Citation Subset: IM |
Affiliation:
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Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Cell Cycle* Epithelial Cells / metabolism* Fibrosis Glomerulonephritis / genetics Humans Kidney / metabolism*, pathology* Kidney Diseases / genetics, pathology Kidney Failure, Acute / genetics Mitogen-Activated Protein Kinase 9 / metabolism Tumor Suppressor Protein p53 / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK074030/DK/NIDDK NIH HHS; DK39773/DK/NIDDK NIH HHS; DK72381/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Tumor Suppressor Protein p53; EC 2.7.1.24/Mitogen-Activated Protein Kinase 9 |
| Comments/Corrections | |
Comment In:
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Nat Med. 2010 May;16(5):523-5
[PMID:
20448575
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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