An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells
- 1 July 2003
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 139 (6), 1085-1094
- https://doi.org/10.1038/sj.bjp.0705339
Abstract
1. We studied the effect of a new angiotensin II type 1 (AT(1)) receptor antagonist, olmesartan medoxomil (olmesartan), on the fibrogenic responses in rat hepatic stellate cells (HSCs) and liver fibrogenesis. 2. Olmesartan (1 mg kg(-1) per day) was orally administered to fibrotic rats, induced by bile duct ligation. Liver hydroxyproline content, the mRNA expression of collagen alpha1(I) and alpha-smooth muscle actin (alpha-SMA), and plasma levels of transforming growth factor-beta1 (TGF-beta1) were significantly reduced by olmesartan treatment, suggesting that olmesartan improved liver fibrosis. Interestingly, AT(1) receptors were found to be expressed in alpha-SMA-positive cells in the fibrotic area of livers in bile duct-ligated rats by immunohistochemical analysis. Olmesartan treatment reduced the number of these cells. 3. In vitro experiments showed that angiotensin II (Ang II) treatment induced proliferation and collagen synthesis, and upregulated the profibrogenic cytokines, TGF-beta1 and connective tissue growth factor (CTGF), in rat primary HSCs. Olmesartan blocked all these effects of Ang II. 4. Based on these results, since activated HSCs were found to express AT(1) receptors and Ang II is thought to play an important role in the pathogenesis of liver fibrosis by binding to these receptors, olmesartan may act as a potent antifibrotic drug to suppress the proliferation, collagen synthesis and the expression of profibrogenic cytokines in activated HSCs by blocking these receptors.Keywords
This publication has 49 references indexed in Scilit:
- Pioglitazone Prevents Early-Phase Hepatic Fibrogenesis Caused by Carbon TetrachlorideBiochemical and Biophysical Research Communications, 2002
- Halofuginone to Prevent and Treat Thioacetamide–Induced Liver Fibrosis in RatsHepatology, 2001
- CIRCULATING TRANSFORMING GROWTH FACTOR β1AS AN INDICATOR OF HEPATIC FUNCTION IMPAIRMENT IN LIVER CIRRHOSISCytokine, 2000
- Local Angiotensin II and Transforming Growth Factor-β1 in Renal Fibrosis of RatsHypertension, 2000
- Effect of Losartan, An Angiotensin Ii Receptor Antagonist, on Portal Pressure in CirrhosisHepatology, 1999
- Captopril reduces collagen and mast cell and eosinophil accumulation in pig serum‐induced rat liver fibrosisPathology International, 1994
- Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.JCI Insight, 1994
- Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by suramin.JCI Insight, 1994
- Angiotensin II receptor-mediated proliferation of cultured human fetal mesangial cellsKidney International, 1991
- Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells.JCI Insight, 1989