Effect of angiotensin AT1 receptor antagonist on D-galactosamine-induced acute liver injury.
1. Acute liver injury is a severe disease in which metabolic homeostasis is affected. The presence of liver cell death triggers a cascade of inflammatory responses leading to various degrees of liver damage. The pathophysiology of liver injury is complex, involving an interplay between parenchymal and non-parenchymal cells. 2. There is increasing evidence for a role of the local renin-angiotensin system (RAS) in liver cell death, inflammatory response and liver regeneration. It has been shown that the local RAS plays an important regulatory role in a variety of tissues. In experimental hepatic fibrogenesis, the angiotensin AT(1) receptor (AT(1)R) blocker losartan has been shown to be able to attenuate transforming growth factor-b1 activity and collagen gene expression. 3. In the present study, using a D-galactosamine (GalN)-induced liver failure rat, AT(1)R were localized around the centrilobular region, which was not evident in normal liver. Blood tests showed an elevation of total bilirubin and alanine aminotransferase. Furthermore, there was an increase in tissue-specific inhibitor of metalloproteinase (TIMP)-1 protein in the liver. Losartan treatment was able to reduce all these parameters. Levels of TIMP-1 protein were reduced by 1.5- and 1.56-fold on Days 1 and 3, respectively (both P < 0.05), in the losartan-treated group relative to the GalN-treated group. The survival rate of the losartan-treated group was significantly higher than that of the GalN-treated group (5 day survival 85 vs 42.5%, respectively; P < 0.05). 4. In conclusion, the AT(1)R blocker losartan suppresses GalN-induced liver injury. This may indicate that AT(1)R blockers may have therapeutic potential in the treatment of acute liver injury.
Chan
Herman
H
Department of Physiology, The Chinese University of Hong Kong, Hong Kong SAR, China. hermanchan@cuhk.edu.hk
Leung
Po-Sing
PS
Tam
Michael S-C
MS
D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005688:Galactosamine / Q000633:toxicity*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013534:Survival; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D044139:Receptor, Angiotensin, Type 2; D019715:Tissue Inhibitor of Metalloproteinase-1; D005688:Galactosamine; D000410:Alanine Transaminase; D019808:Losartan