Cross talk of tumor necrosis factor-alpha and the renin-angiotensin system in tumor necrosis factor-alpha-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(1) receptor mRNA expression were upregulated time-dependently by TNF-alpha. Moreover, angiotensin AT(1) 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(1) receptor. These results suggest that TNF-alpha and the local renin-angiotensin system coordinately stimulate PAI-1 production in hepatocytes. Selective angiotensin AT(1) receptor antagonists inhibit both TNF-alpha- and angiotensin II-induced PAI-1 production in hepatocytes, suggesting a cross talk between both systems.
Takeshita
Yumie
Y
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
Takamura
Toshinari
T
Ando
Hitoshi
H
Hamaguchi
Erika
E
Takazakura
Akiko
A
Matsuzawa-Nagata
Naoto
N
Kaneko
Shuichi
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha