Inhibition of p53 with its specific inhibitor pifithrin‐α prevents hepatic oxidative stress and inflammation, probably via up‐regulating Sirt1/Nrf2 pathway

Abstract

Background and objectiveUp‐regulation of the tumor suppressor p53 has been reported to mediate the diabetic hepatic injury, including oxidative stress and inflammation. However, its underlying mechanisms remain unclear. Nuclear factor erythroid‐derived 2‐like 2 (Nrf2) is a potent factor against diabetic oxidative stress by inducing the expression of its downstream antioxidants. It is revealed that Nrf2 activates its target genes through an antioxidant‐response element (ARE) when Sirtuin 1 (Sirt1) triggers the release of Nrf2 from Nrf2/Keap1 complex. Furthermore, inverse relationship between Sirt1 signaling and p53 protein abundance has been found in high glucose‐exposed hepatic cells. The aim of present study was to explore whether the hepatic protection from diabetes by p53 inhibition with pifithrin‐α is associated with up‐regulation of Sirt1/Nrf2 pathway in type 1 diabetic mice.Methods and ResultsFVB mice were treated with five daily injections of 50 mg/kg streptozotocin to induce type 1 diabetes. Both hyperglycemic and age‐matched control mice were treated with or without pifithrin‐α five times a week for 2 months and then kept without treatment until 3 months. At three months, diabetes significantly increased serum ALT activity, hepatic 3‐NT, 4‐HNE, IL‐6 and TNF‐α expressions, which was significantly prevented by inhibition of p53 expression with pifithrin‐α in diabetic mice. Mechanistically, the inhibition of p53 reversed diabetes‐increased hepatic expression of Keap1 and p47 phox and decreased Sirt1 expression and Nrf2 expression and function.ConclusionsThese results demonstrate that the inhibition of p53‐mediated down‐regulation of Sirt1/Nrf2 pathway by administration of diabetic mice with p53 specific inhibitor can effectively prevent the development of hepatic oxidative stress and inflammation. Therefore, intervention targeting to p53 may be a potential therapy for diabetic hepatic injury.Support or Funding InformationThis work was supported in part by the Scholarship awarded by China Scholarship Council (No. 201508330753), and the grant awarded by National Natural Science Foundation of China (No. 81470495).