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

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Abstract
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
Funding Information
  • FONDECYT (1120380, 1110426, 11080212, CARE PFB12/2007, CONICYT AT-24090192, MDA 89419)

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