ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats.
OBJECTIVE
Non-alcoholic steatohepatitis (NASH), which is a common liver disease in industrialized countries, is associated with obesity, hypertension, and type-2 diabetes (metabolic syndrome). Since angiotensin II (ANG II) has been suggested to play an important role in liver inflammation and fibrosis, the purpose of this study was to investigate whether therapy against renin-angiotensin system (RAS) may provide some beneficial effect in liver of an animal model of metabolic syndrome.


METHODS
For 6 months, obese Zucker rats (OZRs) were treated as follows: OZR-group, OZR + Perindopril (P) group, OZR + Irbesartan (IRB) group, OZR + Amlodipine (AML) group, and lean Zucker rats (LZRs) group as a control. Livers were evaluated by immunohistochemistry techniques using corresponding antibodies.


RESULTS
All treated groups showed a similar reduction in blood pressure compared to untreated OZR. Therapy either with IRB or P improves insulin sensitivity and reduces hepatic enzyme level with respect to untreated OZR. Conversely, AML failed to modify both parameters. Untreated OZR displayed higher hepatic ANG II levels and steatosis together with a marked increase in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-beta1) level compared to LZR. Following RAS inhibition either by P or IRB, a significant reduction (P < 0.01) in the immunostaining of TNF-alpha, IL-6 and TGF-beta1 compared to untreated OZR was observed.


CONCLUSIONS
These results indicate that ANG II expression is increased in the liver of these animals with steatohepatitis. Furthermore, RAS control by either angiotensin-converting enzyme inhibition or AT1 receptor blockade seems to provide a beneficial modulation concerning the inflammatory response to liver injury in this model. Consequently, blockade of RAS could be a new approach to prevent or to treat patients with NASH.
Toblli
Jorge E
JE
Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina. jorgetoblli@fibertel.com.ar
Muñoz
Marina C
MC
Cao
Gabriel
G
Mella
José
J
Pereyra
Lisandro
L
Mastai
Ricardo
R
D017311:Amlodipine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D000077405:Irbesartan; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy; D009765:Obesity / Q000188:drug therapy*; D020913:Perindopril / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D015850:Interleukin-6; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D017311:Amlodipine; D000077405:Irbesartan; D020913:Perindopril