Document Detail


Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs.
MedLine Citation:
PMID:  23207693     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Blockade of transforming growth factor-β (TGF-β) signaling by Smad7 gene therapy is known to prevent experimental renal fibrosis. This study investigated whether Smad7 suppresses renal fibrosis via altering the renal expression of fibrosis-related microRNAs. Application of gene therapy into diseased kidneys of obstructive nephropathy and kidney cells by overexpressing Smad7 restored miR-29b but inhibited the expression of miR-192 and miR-21, resulting in blockade of renal fibrosis. Furthermore, Smad7 overexpression also suppressed advanced glycated end products- and angiotensin II-regulated expression of these microRNAs. In contrast, disruption of Smad7 gene in mice demonstrated opposite results by enhancing the loss of miR-29b and upregulation of miR-192 and miR-21, resulting in promotion of renal fibrosis in ligated kidneys of a model of obstructive nephropathy. More importantly, treatment with anti-miR-29b, miR-21 and miR-192 mimics in Smad7 overexpressing tubular epithelial cells abrogated the suppressive function of Smad7 on renal fibrosis, suggesting that these microRNAs act downstream of Smad7 to override the Smad7 function. In conclusion, Smad7 protects kidneys from fibrosis by regulating TGF-β/Smad3-mediated renal expression of miR-21, miR-192, and miR-29b. Restored renal miR-29b but suppressed miR-192 and miR-21 may be a mechanism by which gene therapy with Smad7 inhibits renal fibrosis.
Authors:
Arthur C K Chung; Yuan Dong; Weiqin Yang; Xiang Zhong; Rong Li; Hui Y Lan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-04
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-01     Completed Date:  2013-08-07     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  388-98     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Line
Epithelial Cells / cytology,  metabolism
Fibrosis
Gene Expression Regulation
Gene Transfer Techniques
Genetic Therapy
Immunohistochemistry
In Situ Hybridization
Kidney Diseases / genetics,  pathology,  prevention & control*
Mice
Mice, Knockout
MicroRNAs / genetics*,  metabolism
Rats
Reverse Transcriptase Polymerase Chain Reaction
Smad7 Protein / genetics*,  metabolism
Transforming Growth Factor beta1 / genetics*,  metabolism
Chemical
Reg. No./Substance:
0/MIRN21 microRNA, mouse; 0/MIRN29 microRNA, mouse; 0/MicroRNAs; 0/Mirn192 microRNA, mouse; 0/Smad7 Protein; 0/Smad7 protein, mouse; 0/Transforming Growth Factor beta1
Comments/Corrections

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