The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

Abstract

Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.

• Authors: Saliha Sena Karcioglu, Saziye Sezin Palabiyik, Yasin Bayir, Emre Karakus, Tolga Mercantepe, Zekai Halici, Abdulmecit Albayrak
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 117 Issue 3 Pg. 638-46 (Mar 2016) ISSN: 1097-4644 [Electronic] United States
• PMID: 26280784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Amides
• Antioxidants
• Fumarates
• Oxidants
• Angiotensin II
• Acetaminophen
• aliskiren
• Aspartate Aminotransferases
• Alanine Transaminase
• Renin

Topics

• Acetaminophen (toxicity)
• Alanine Transaminase (blood)
• Amides (pharmacology, therapeutic use)
• Angiotensin II (blood)
• Animals
• Antioxidants (metabolism)
• Aspartate Aminotransferases (blood)
• Chemical and Drug Induced Liver Injury (blood, drug therapy)
• Fumarates (pharmacology, therapeutic use)
• Liver (drug effects, metabolism)
• Male
• Oxidants (metabolism)
• Rats, Wistar
• Renin (antagonists & inhibitors, blood)
• Renin-Angiotensin System (drug effects)