Cross talk of tumor necrosis factor-α and the renin–angiotensin system in tumor necrosis factor-α-induced plasminogen activator inhibitor-1 production from hepatocytes

• Published in: European journal of pharmacology 2008-01, Vol.579 (1), p.426-432
• Main Authors: Takeshita, Yumie, Takamura, Toshinari, Ando, Hitoshi, Hamaguchi, Erika, Takazakura, Akiko, Matsuzawa-Nagata, Naoto, Kaneko, Shuichi
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin type 1 receptor antagonist; Cell Line; Diabetes Mellitus, Type 2 - complications; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Hepatocytes - metabolism; Humans; Insulin Resistance - physiology; Liver; Liver - metabolism; Liver - pathology; Male; Middle Aged; Obesity - complications; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitor-1; Renin-Angiotensin System - physiology; Renin–angiotensin system; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.11.016

Tumor necrosis factor (TNF)-α and local activation of the renin–angiotensin system may contribute to insulin resistance and atherosclerosis. In this study, we investigated the involvement of these mediators in the liver. We found that the gene expression of renin–angiotensin system components, together with that of plasminogen activator inhibitor (PAI)-1, is upregulated in the liver of patients with obesity and type 2 diabetes. We next examined the role of the renin–angiotensin system on TNF-α-induced PAI-1 production in the nonmalignant human hepatocyte cell line THLE-5b. THLE-5b cells expressed genes encoding renin–angiotensin system components including angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin type 1 (AT 1) receptor. ACE, angiotensinogen, and angiotensin AT 1 receptor mRNA expression were upregulated time-dependently by TNF-α. Moreover, angiotensin AT 1 receptor antagonist dose-dependently inhibited TNF-α-induced PAI-1 production. Interestingly, high-dose olmesartan, but not candesartan, reduced the increased expression of the angiotensin AT 1 receptor. These results suggest that TNF-α and the local renin–angiotensin system coordinately stimulate PAI-1 production in hepatocytes. Selective angiotensin AT 1 receptor antagonists inhibit both TNF-α- and angiotensin II-induced PAI-1 production in hepatocytes, suggesting a cross talk between both systems.