Allopurinol ameliorates liver injury in type 1 diabetic rats through activating Nrf2.

Abstract

Hyperglycemia-induced oxidative stress plays important roles in the development of non-alcoholic fatty liver disease (NAFLD), which is a common complication in diabetic patients. The Nrf2-Keap1 pathway is important for cell antioxidant protection, while its role in exogenous antioxidant mediated protection against NAFLD is unclear. We thus, postulated that antioxidant treatment with allopurinol (ALP) may attenuate diabetic liver injury and explored the underlying mechanisms. Control (C) and streptozotocin (STZ)-induced diabetes rats (D) were untreated or treated with ALP for 4 weeks starting at 1 week after diabetes induction. Serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), production of lipid peroxidation product malondialdehyde (MDA), and serum superoxide dismutase (SOD) were detected. Liver protein expressions of cleaved-caspase 3, IL-1β, nuclear factor-erythroid-2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), P62, Kelch-like ECH-associated protein 1 (Keap1), and LC3 were analyzed. In vitro, cultured rat normal hepatocytes BRL-3A were grouped to normal glucose (5.5 mM, NG) or high glucose (25 mM, HG) and treated with or without allopurinol (100 µM) for 48 h. Rats in the D group demonstrated liver injury evidenced as increased serum levels of ALT and AST. Diabetes increased apoptotic cell death, enhanced liver protein expressions of cleaved-caspase 3 and IL-1β with concomitantly increased production of MDA while serum SOD content was significantly reduced (all P < 0.05 vs C). In the meantime, protein levels of Nrf2, HO-1, and P62 were reduced while Keap1 and LC3 were increased in the untreated D group as compared to control (P < 0.05 vs C). And all the above alterations were significantly attenuated by ALP. Similar to our findings obtained from in vivo study, we got the same results in in vitro experiments. It is concluded that ALP activates the Nrf2/p62 pathway to ameliorate oxidative stress and liver injury in diabetic rats.

• Authors: Fei Zeng, Jierong Luo, Hong Han, Wenjie Xie, Lingzhi Wang, Ronghui Han, Hao Chen, Yin Cai, Huansen Huang, Zhengyuan Xia
• Journal: International journal of immunopathology and pharmacology (Int J Immunopathol Pharmacol) 2021 Jan-Dec Vol. 35 Pg. 20587384211031417 ISSN: 2058-7384 [Electronic] England
• PMID: 34240649 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Enzyme Inhibitors
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Allopurinol

Topics

• Allopurinol (therapeutic use)
• Animals
• Antioxidants (metabolism)
• Apoptosis (drug effects)
• Cell Line
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 1 (complications)
• Enzyme Inhibitors (therapeutic use)
• Hepatocytes (drug effects, metabolism)
• Liver Function Tests
• Lung Injury (etiology, prevention & control)
• Male
• NF-E2-Related Factor 2 (drug effects)
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley