Angiotensin II increases mRNA levels of all TGF-beta isoforms in quiescent and activated rat hepatic stellate cells.
AII (angiotensin II) is a vasoactive peptide that plays an important role in the development of liver fibrosis mainly by regulating profibrotic cytokine expression such as TGF-beta (transforming growth factor-beta). Activated HSCs (hepatic stellate cells) are the major cell type responsible for ECM (extracellular matrix) deposition during liver fibrosis and are also a target for AII and TGF-beta actions. Here, we studied the effect of AII on the mRNA levels of TGF-beta isoforms in primary cultures of rat HSCs. Both quiescent and activated HSCs were stimulated with AII for different time periods, and mRNA levels of TGF-beta1, TGF-beta2 and TGF-beta3 isoforms were evaluated using RNaseI protection assay. The mRNA levels of all TGF-beta isoforms, particularly TGF-beta2and TGF-beta3, were increased after AII treatment in activated HSCs. In addition, activated HSCs were able to produce active TGF-beta protein after AII treatment. The mRNA expression of TGF-beta isoforms induced by AII required both ERK1/2 and Nox (NADPH oxidase) activation but not PKC (protein kinase C) participation. ERK1/2 activation induced by AII occurs via AT1 receptors, but independently of either PKC and Nox activation or EGFR (epidermal growth factor receptor) transactivation. Interestingly, AII has a similar effect on TGF-beta expression in quiescent HSCs, although it has a smaller but significant effect on ERK1/2 activation in these cells.
Moreno-Alvarez
Paola
P
Departamento de Biologa Celular y Desarrollo, Instituto de Fisiologa Celular, Universidad Nacional Autnoma de Mxico, Mxico, D.F. 04510, Mexico.
Sosa-Garrocho
Marcela
M
Briones-Orta
Marco A
MA
González-Espinosa
Claudia
C
Medina-Tamayo
Jaciel
J
Molina-Jijón
Eduardo
E
Pedraza-Chaverri
José
J
Macías-Silva
Marina
M
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000378:metabolism*; D008156:Luciferases; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D008156:Luciferases; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3