Document Detail


TGF-{beta}1 protects against mesangial cell apoptosis via induction of autophagy.
MedLine Citation:
PMID:  20876581     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Autophagy can lead to cell death in response to stress, but it can also act as a protective mechanism for cell survival. We show that TGF-β1 induces autophagy and protects glomerular mesangial cells from undergoing apoptosis during serum deprivation. Serum withdrawal rapidly induced autophagy within 1 h in mouse mesangial cells (MMC) as determined by increased microtubule-associated protein 1 light chain 3 (LC3) levels and punctate distribution of the autophagic vesicle-associated-form LC3-II. We demonstrate that after 1 h there was a time-dependent decrease in LC3 levels that was accompanied by induction of apoptosis, evidenced by increases in cleaved caspase 3. However, treatment with TGF-β1 resulted in induction of the autophagy protein LC3 while suppressing caspase 3 activation. TGF-β1 failed to rescue MMC from serum deprivation-induced apoptosis upon knockdown of LC3 by siRNA and in MMC from LC3 null (LC3(-/-)) mice. We show that TGF-β1 induced autophagy through TAK1 and Akt activation, and inhibition of PI3K-Akt pathway by LY294002 or dominant-negative Akt suppressed LC3 levels and enhanced caspase 3 activation. TGF-β1 also up-regulated cyclin D1 and E protein levels while down-regulating p27, thus stimulating cell cycle progression. Bafilomycin A1, but not MG132, blocked TGF-β1 down-regulation of p27, suggesting that p27 levels were regulated through autophagy. Taken together, our data indicate that TGF-β1 rescues MMC from serum deprivation-induced apoptosis via induction of autophagy through activation of the Akt pathway. The autophagic process may constitute an adaptive mechanism to glomerular injury by inhibiting apoptosis and promoting mesangial cell survival.
Authors:
Yan Ding; Jin Kuk Kim; Sung Il Kim; Hee-Jun Na; Soo Young Jun; Seon Jin Lee; Mary E Choi
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-28
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2010-12-30     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  37909-19     Citation Subset:  IM    
Affiliation:
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Autophagy*
Caspase 3 / genetics,  metabolism
Cells, Cultured
Male
Mesangial Cells / cytology*,  metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Microtubule-Associated Proteins / genetics,  metabolism
Transforming Growth Factor beta1 / metabolism*
Grant Support
ID/Acronym/Agency:
R01 DK57661/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/MAP1LC3 protein, mouse; 0/Microtubule-Associated Proteins; 0/Transforming Growth Factor beta1; EC 3.4.22.-/Caspase 3
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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