Targeting PI3K/p‐Akt/eNOS, Nrf2/HO‐1, and NF‐κB/p53 signaling pathways by angiotensin 1–7 protects against liver injury induced by ischemia–reperfusion in rats

Abstract The liver is an important organ, and hepatic ischemia–reperfusion (IR) injury is a frequent pathophysiological process that can cause significant morbidity and mortality. Thus, our study aimed to investigate the effect of targeting PI3K/p‐Akt/eNOS (phosphoinositide 3‐kinase/phospho‐protein kinase B/endothelial nitric oxide synthase), Nrf2/HO‐1 (nuclear factor‐erythroid 2‐related factor‐2/heme oxygenase‐1), and NF‐κB/p53 (nuclear factor‐κB/tumor protein 53) signaling pathways by using angiotensin (1–7) [ang‐(1–7)] against hepatic injury induced by IR. Thirty‐two male rats were included in sham group, ang‐(1–7)‐treated group, hepatic IR group, and hepatic IR group treated with ang‐(1–7). The levels of hepatic ang‐(1–7), angiotensin II (Ang II), angiotensin‐converting enzyme 2 (ACE2), HO‐1, malondialdehyde (MDA), PI3K, and p‐Akt were assessed. The expressions of eNOS and B‐cell leukemia/lymphoma‐2 (BCL‐2) in the liver were determined. Histological assessment and immunohistochemical expression of NF‐κB, p53, and Nrf2 were carried out. The levels of reduced glutathione (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) in serum were estimated. Results showed that administration of ang‐(1–7) to hepatic IR rats led to significant amelioration of hepatic damage through a histological evaluation that was associated with significant upregulation of the expressions of PI3K/p‐Akt/eNOS and Nrf2/HO‐1 with downregulation of NF‐κB/p53 signaling pathways. In conclusion, PI3K/p‐Akt/eNOS and Nrf2/HO‐1 signaling pathways are involved in the protective effects of ang‐(1–7) against hepatic damage induced by IR. Therefore, ang‐(1–7) can be used to prevent hepatic IR, which occurs in certain conditions such as liver transplantation, hemorrhagic shock, and severe infection.