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

Tumor necrosis factor (TNF)-alpha 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-alpha-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, receptor mRNA expression were upregulated time-dependently by TNF-alpha. Moreover, angiotensin AT, receptor antagonist dose-dependently inhibited TNF-alpha-induced PAI-1 production. Interestingly, high-dose olmesartan, but not candesartan, reduced the increased expression of the angiotensin AT, receptor. These results suggest that TNF-alpha. and the local renin-angiotensin system coordinately stimulate PAI-1 production in hepatocytes. Selective angiotensin AT, receptor antagonists inhibit both TNF-alpha- and angiotensin II-induced PAI-1 production in hepatocytes., suggesting a cross talk between both systems. (c) 2007 Elsevier B.V. All rights reserved.