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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Angiotensin II Type 1 Receptor-Dependent Nuclear Factor-κB Activation-Mediated Proinflammatory Actions in a Rat Model of Obstructive Acute Pancreatitis

Yuk Cheung Chan and Po Sing Leung
Journal of Pharmacology and Experimental Therapeutics October 2007, 323 (1) 10-18; DOI: https://doi.org/10.1124/jpet.107.124891
Yuk Cheung Chan
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Po Sing Leung
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Abstract

Angiotensin II is a key mediator of inflammation, and nuclear factor-κB (NF-κB) 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-κB 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-κB inhibitory subunits (IκBα and IκBβ) and phospho-NF-κB p65, κB-related proteins (intercellular adhesion molecule-1, cyclooxygenas-2, and interleukin-1), and NADPH oxidase isoforms p67 and p22 were examined by Western blot. Nuclear κB 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-κB-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 IκBβ and elevation of phospho-NF-κB p65 protein expression as well as the enhanced nuclear κB binding activity and elevated levels of κB-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-κB activation; thus, it might ultimately promote proinflammatory actions during AP pathogenesis.

Footnotes

  • This work was fully supported by a competitive earmarked research grant from the Research Grants Council of Hong Kong, Project CUHK 4364/04M (to P.S.L.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.124891.

  • ABBREVIATIONS: AP, acute pancreatitis; RAS, renin-angiotensin system; AT1 receptor, angiotensin II type 1 receptor; ROS, reactive oxygen species; NF-κB, nuclear factor-κB; IκBα, inhibitory subunit α of NF-κB; IκBβ, inhibitory subunit β of NF-κB; CBPD, common biliopancreatic duct; ICAM, intercellular adhesion molecule; COX, cyclooxygenase; EMSA, electrophoretic mobility shift assay; MPO, myeloperoxidase; GSH, glutathione; IL, interleukin-1; EXP 3179, 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxaldehyde (C22H21ClN6O).

    • Received April 29, 2007.
    • Accepted July 3, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Angiotensin II Type 1 Receptor-Dependent Nuclear Factor-κB Activation-Mediated Proinflammatory Actions in a Rat Model of Obstructive Acute Pancreatitis

Yuk Cheung Chan and Po Sing Leung
Journal of Pharmacology and Experimental Therapeutics October 1, 2007, 323 (1) 10-18; DOI: https://doi.org/10.1124/jpet.107.124891

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Angiotensin II Type 1 Receptor-Dependent Nuclear Factor-κB Activation-Mediated Proinflammatory Actions in a Rat Model of Obstructive Acute Pancreatitis

Yuk Cheung Chan and Po Sing Leung
Journal of Pharmacology and Experimental Therapeutics October 1, 2007, 323 (1) 10-18; DOI: https://doi.org/10.1124/jpet.107.124891
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