Int J Med Sci 2020; 17(18):3098-3106. doi:10.7150/ijms.49373 This issue

Research Paper

Angiotensin II receptor Neprilysin inhibitor (LCZ696) compared to Valsartan attenuates Hepatotoxicity in STZ-induced hyperglycemic rats

Faleh Alqahtani#, Mohamed Mohany#, Abdullah F Alasmari, Ahmed Z. Alanazi, Osamah M. Belali, Mohammed M Ahmed, Salim S Al-Rejaie

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh - 1145, Saudi Arabia.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Alqahtani F, Mohany M, Alasmari AF, Alanazi AZ, Belali OM, Ahmed MM, Al-Rejaie SS. Angiotensin II receptor Neprilysin inhibitor (LCZ696) compared to Valsartan attenuates Hepatotoxicity in STZ-induced hyperglycemic rats. Int J Med Sci 2020; 17(18):3098-3106. doi:10.7150/ijms.49373. Available from

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Background and objectives: Although diabetic-induced hepatotoxicity is less common, it can be included in the list of target organ pathologies associated with diabetes. This study aimed to investigate the potential therapeutic role of sacubitril/valsartan (LCZ696) in modulating oxidative and inflammatory injuries and liver fibrosis in STZ-induced hyperglycemic rats in comparison to valsartan alone.

Materials and Methods: Following the induction of diabetes using a single dose of streptozotocin (STZ), STZ-induced hyperglycemic animals were administered LCZ696 or valsartan for 6 weeks. Glucose, transaminases, lipid profile, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin - 6 (IL-6), were estimated using the obtained serum. Oxidative stress biomarkers including thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were measured in the liver homogenate. Additionally, the levels of TNF-α, IL-1β, IL-6, and nuclear factor - kappa β (NF-κB) levels were estimated in hepatic tissue. To assess the general histopathological changes, harvested liver tissue was treated with hematoxylin and eosin or Masson's trichrome staining to detect fibrosis.

Results: STZ-induced hyperglycemic rats demonstrated high blood glucose, dyslipidemia, and significant elevation in hepatic transaminases, proinflammatory cytokines, NF-κB, lipid peroxidation, and hepatic fibrosis, with impairment in antioxidant enzymes. In STZ-induced hyperglycemic rats, the administration of LCZ696 ameliorated hyperglycemia, dyslipidemia, improved liver functions, and boosted antioxidants enzymes. Furthermore, LCZ696 therapy attenuated oxidation, inflammation, progression of liver injury, and hepatic fibrosis. LCZ696 was superior to valsartan in reducing AST, hepatic fibrosis, tissue IL-1β, TNF-α and NF-κB. In addition, compared with the valsartan group, LCZ696 significantly increased the antioxidant parameters such as GSH, SOD, CAT and GPx.

Conclusion: Collectively, our data demonstrated that LCZ696 could suppress the progression of diabetes-induced hepatic fibrosis, correlating with reduced oxidative stress, hepatic inflammation and NF-κB compared with valsartan alone.

Keywords: Hyperglycemic rats, LCZ696, valsartan, oxidative stress, inflammation, hepatic fibrosis