title: Angiotensin II type 1 receptor-dependent nuclear factor-kappaB activation-mediated proinflammatory actions in a rat model of obstructive acute pancreatitis.
abstract: Angiotensin II is a key mediator of inflammation, and nuclear factor-kappaB (NF-kappaB) plays a critical role in various inflammatory diseases, including acute pancreatitis (AP). This study sought to elucidate the mechanism mediating angiotensin II involvement in angiotensin II type 1 (AT1) receptor-mediated NF-kappaB activation, and ultimately in proinflammatory actions of AP pathogenesis. A rat model of obstructive pancreatitis was induced by ligation of the common biliopancreatic duct. Pancreatic injury was determined by assessing pancreatic histology, myeloperoxidase activity, and serum interleukin-6. Protein levels of pancreatic angiotensinogen and AT1 receptor as well as NF-kappaB inhibitory subunits (IkappaBalpha and IkappaBbeta) and phospho-NF-kappaB p65, kappaB-related proteins (intercellular adhesion molecule-1, cyclooxygenase-2, and interleukin-1), and NADPH oxidase isoforms p67 and p22 were examined by Western blot. Nuclear kappaB binding activity and degree of oxidative stress were determined by electrophoretic mobility shift assay and glutathione/nitrotyrosine examination, respectively. The effects of losartan, an AT1 receptor antagonist, on NF-kappaB-mediated proinflammatory actions were also assessed. Induction of AP was associated with a time-dependent increase in pancreatic angiotensinogen levels. AT1 receptor blockade with losartan improved the pancreatic histological damage, myeloperoxidase activity, and serum interleukin-6. Losartan treatment also reduced AP-associated depletion of IkappaBbeta and elevation of phospho-NF-kappaB p65 protein expression as well as the enhanced nuclear kappaB binding activity and elevated levels of kappaB-related proteins. In addition, losartan treatment suppressed pancreatic glutathione and nitrotyrosine levels, which were consistent with decreased NADPH oxidase expression. These data provide substantial evidence that angiotensin II is involved in AT1 receptor-mediated NADPH oxidase-dependent NF-kappaB activation; thus, it might ultimately promote proinflammatory actions during AP pathogenesis.
authors.affiliation: Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors.forename: Yuk Cheung
authors.initials: YC
authors.lastname: Chan
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000208:Acute Disease; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis*; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016328:NF-kappa B; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan