Angiotensin-(1–7) ameliorates intestinal barrier dysfunction by activating the Keap1/Nrf2/HO-1 signaling pathway in acute pancreatitis

Background Intestinal barrier dysfunction is a serious complication associated with acute pancreatitis (AP). Angiotensin (Ang)-(1–7) plays a protective role in the intestinal barrier, but the underlying mechanism remains clear. This study investigated the impact of Ang-(1–7) on AP-induced intestinal dysfunction and its involvement in the Keap1/Nrf2/HO-1 pathway. Methods and results We studied caerulein- and lipopolysaccharide (LPS)-induced AP in mice and an epithelial cell line (IEC-6) from the small intestinal crypt of rats. Ang-(1–7) was administered orally or via the tail vein. IEC-6 cells were divided into five groups: control; LPS; LPS + Ang-(1–7); LPS + Ang-(1–7) + ML385 (an Nrf2 inhibitor); and LPS + ML385. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. The expression of intestinal barrier-associated proteins and Keap1/Nrf2/HO-1 pathway constituents was assessed by RT-PCR and western blotting. The peroxide and antioxidant activities in the IEC-6 cells were measured. Compared to those in AP mice, Ang-(1–7) diminished the intestinal levels of proinflammatory factors (interleukin-1β and tumor necrosis factor α) and serum levels of intestine permeability ( d -lactate). Ang-(1–7) increased the expression of barrier-associated proteins (aquaporin-1, claudin-1, and occludin) compared to those in the AP and LPS group. Moreover, Ang-(1–7) promoted the Keap/Nrf2/HO-1 pathway, which resulted in significantly reduced malondialdehyde and increased superoxide dismutase levels.. However, ML385 abolished the effects of Ang-(1–7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway. Conclusions Ang-(1–7) reduces AP-induced intestinal inflammation and oxidative injuries by activating the Keap1/Nrf2/HO-1 pathway.