title: Fibrotic response induced by angiotensin-II requires NAD(P)H oxidase-induced reactive oxygen species (ROS) in skeletal muscle cells.
abstract: Fibrotic disorders are typified by excessive connective tissue and extracellular matrix (ECM) deposition that precludes normal healing processes in different tissues. Angiotensin-II (Ang-II) is involved in the fibrotic response. Several muscular dystrophies are characterized by extensive fibrosis. However, the exact role of Ang-II in skeletal muscle fibrosis is unknown. Here we show that myoblasts responded to Ang-II by increasing protein levels of connective tissue growth factor (CTGF/CCN2), collagen-III and fibronectin. These Ang-II-induced pro-fibrotic effects were mediated by AT-1 receptors. Remarkably, Ang-II induced reactive oxygen species (ROS) via a NAD(P)H oxidase-dependent mechanism, as shown by inhibition of ROS production via the NAD(P)H oxidase inhibitors diphenylene iodonium (DPI) and apocynin. This increase in ROS is critical for Ang-II-induced fibrotic effects, as indicated by the decrease in Ang-II-induced CTGF and fibronectin levels by DPI and apocynin. We also show that Ang-II-induced ROS production and fibrosis require PKC activity as indicated by the generic PKC inhibitor chelerythrine. These results strongly suggest that the fibrotic response induced by Ang-II is mediated by AT-1 receptor and requires NAD(P)H-induced ROS in skeletal muscle cells.
authors.affiliation: Centro de Genética Humana (CGH), Facultad de Medicina-Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile. ccabello@udd.cl
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
authors.forename: María José
authors.initials: MJ
authors.lastname: Acuña
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Morales
authors.forename: Alvaro
authors.initials: A
authors.lastname: Becerra
authors.forename: Felipe
authors.initials: F
authors.lastname: Simon
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D019255:NADPH Oxidases