Transforming growth factor type beta 1 increases the expression of angiotensin II receptor type 2 by a SMAD- and p38 MAPK-dependent mechanism in skeletal muscle

Excessive deposition of extracellular matrix (ECM) proteins, a condition known as fibrosis, is a hallmark of Duchenne muscular dystrophy. Among the factors that trigger muscle fibrosis are transforming growth factor beta (TGF‐β) and angiotensin II (Ang‐II). Ang‐II belongs to the renin‐angiotensin sy...

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Published in:	BioFactors (Oxford) Vol. 39; no. 4; pp. 467 - 475
Main Authors:	Painemal, Paula, Acuña, María José, Riquelme, Cecilia, Brandan, Enrique, Cabello-Verrugio, Claudio
Format:	Journal Article
Language:	English
Published:	Netherlands Blackwell Publishing Ltd 01-07-2013
Subjects:	Animals AT-2 receptor Cell Line Fibrosis Gene Expression Male Mice Mice, Inbred C57BL Mice, Inbred mdx Muscle, Skeletal - pathology Muscular Dystrophy, Duchenne - metabolism Muscular Dystrophy, Duchenne - pathology Myoblasts - metabolism p38 Mitogen-Activated Protein Kinases - metabolism Receptor, Angiotensin, Type 1 - metabolism Receptor, Angiotensin, Type 2 - genetics Receptor, Angiotensin, Type 2 - metabolism Renin-Angiotensin System Signal Transduction skeletal muscle Smad Proteins - metabolism TGF-β Transforming Growth Factor beta1 - pharmacology Transforming Growth Factor beta1 - physiology TGF-β AT-2 receptor skeletal muscle Fibrosis
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Summary:	Excessive deposition of extracellular matrix (ECM) proteins, a condition known as fibrosis, is a hallmark of Duchenne muscular dystrophy. Among the factors that trigger muscle fibrosis are transforming growth factor beta (TGF‐β) and angiotensin II (Ang‐II). Ang‐II belongs to the renin‐angiotensin system, and its biological effects are exerted by Ang‐II receptors type 1 and type 2 (AT‐1 and AT‐2, respectively). This study aims to determine the effect of TGF‐β1 on the expression of AT‐1 and AT‐2 receptor in skeletal muscle. C2C12 myoblasts exposed to TGF‐β1 showed a dose‐dependent increase in AT‐2 expression but with no effect on AT‐1 levels. Injection of TGF‐β1 in the skeletal muscle of mice increased the levels of AT‐2 and ECM protein but unchanged AT‐1 levels. We also detected higher expression levels of AT‐2 receptor in dystrophic skeletal muscle of mdx mice than in normal mice. The induction of AT‐2 was mediated by the canonical TGF‐β pathway because under the inhibitory conditions of the kinase activity of TGFβ receptor I or the knockdown of Smad2/3 levels, TGF‐β‐induced AT‐2 receptor increase was strongly inhibited. Furthermore, we demonstrated that p38MAPK activity in response to TGF‐β is also required for AT‐2 increase as evaluated by a p38MAPK inhibitor. Our results show that the levels of AT‐2 but not AT‐1 receptor are modulated by the pro‐fibrotic factor TGF‐β1 in myoblasts and mouse skeletal muscle. This finding suggests that AT‐2 might be involved in the physiopathology of fibrosis in dystrophic skeletal muscle. © 2013 BioFactors, 39(4):467–475, 2013
Bibliography:	FONDECYT - No. 1120380; No. 1110426; No. 11080212; No. CARE PFB12/2007; No. CONICYT AT-24090192; No. MDA 89419 ArticleID:BIOF1087 istex:0A0E38DA76E1419291E7A18C9B361B6369C431F9 ark:/67375/WNG-B2K735QF-S ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0951-6433 1872-8081
DOI:	10.1002/biof.1087