title: Involvement of angiotensin II and reactive oxygen species in pancreatic fibrosis.
abstract: BACKGROUND
  Pancreatic cancers often develop in the context of pancreatic fibrosis caused by chronic pancreas inflammation, which also results in the accumulation of reactive oxygen species (ROS), pancreatic parenchymal cell death, and stellate cell activation. Angiotensin II, which is converted from angiotensin I by the angiotensin-converting enzyme (ACE), stimulates ROS production via NADPH oxidase. In stellate cells, angiotensin II activates the stress-activated protein kinase p38. However, the molecular mechanism by which angiotensin II regulates pancreatic inflammation and fibrosis remains to be determined.
  
  
  METHODS
  Wistar Bonn/Kobori (WBN/Kob) rats spontaneously develop chronic pancreatic inflammation. To examine whether blockade of the renin-angiotensin system affects the development of pancreatic fibrosis, WBN/Kob rats were given angiotensin II type 1 receptor (AT1R) blocker or ACE inhibitor (ACEI). Next, we assessed the role of angiotensin II and its possible downstream target p38α in stellate cell activation using primary stellate cells.
  
  
  RESULTS
  Treatment with AT1R blocker and ACEI prevented the development of chronic pancreatitis and fibrosis. In stellate cells, angiotensin II upregulated the expression of angiotensin II receptors, α-smooth muscle actin (SMA) and transforming growth factor-β. In addition, p38α was found to be essential to collagen type I production and α-SMA expression. ROS accumulation is enhanced in chronic pancreatic inflammation, which increases the risk of pancreatic cancer.
  
  
  CONCLUSIONS
  Inhibition of the angiotensin II signaling pathway might be a promising strategy to prevent pancreatic fibrogenesis and subsequent carcinogenesis.
authors.affiliation: Department of Gastroenterology and Hepatology, Faculty of Medicine, Kinki University, Osakasayama, Osaka, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fukuta
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.forename: Masatomo
authors.initials: M
authors.lastname: Kimura
authors.forename: Ah-Mee
authors.initials: AM
authors.lastname: Park
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Munakata
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015536:Down-Regulation; D005355:Fibrosis; D008297:Male; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D017382:Reactive Oxygen Species; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases