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

by Selleckchem | Aug 27 2023

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.

Comments:

The study you mentioned investigated the impact of Angiotensin (Ang)-(1-7) on intestinal barrier dysfunction associated with acute pancreatitis (AP) and explored its involvement in the Keap1/Nrf2/HO-1 pathway. The researchers conducted experiments using both mice and an epithelial cell line derived from the small intestine of rats (IEC-6 cells).

In the mouse model of AP induced by caerulein and lipopolysaccharide (LPS), Ang-(1-7) was administered orally or through the tail vein. The researchers also used the IEC-6 cell line and divided the cells into five groups: control, LPS only, LPS + Ang-(1-7), LPS + Ang-(1-7) + ML385 (an Nrf2 inhibitor), and LPS + ML385.

The researchers assessed the histopathology scores of the pancreas and intestines using the Schmidt and Chiu scores. They analyzed the expression of intestinal barrier-associated proteins and components of the Keap1/Nrf2/HO-1 pathway using RT-PCR and western blotting. In addition, peroxide and antioxidant activities were measured in the IEC-6 cells.

The results showed that Ang-(1-7) administration reduced the intestinal levels of proinflammatory factors such as interleukin-1β and tumor necrosis factor α, as well as serum levels of D-lactate, which is an indicator of intestinal permeability. Ang-(1-7) also increased the expression of barrier-associated proteins including aquaporin-1, claudin-1, and occludin compared to the AP and LPS group. Furthermore, Ang-(1-7) promoted the activation of the Keap1/Nrf2/HO-1 pathway, leading to a decrease in malondialdehyde levels (a marker of oxidative damage) and an increase in superoxide dismutase levels (an antioxidant enzyme).

However, when the Nrf2 inhibitor ML385 was used, it abolished the effects of Ang-(1-7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway, indicating that the protective effects of Ang-(1-7) were dependent on the activation of this pathway.

In conclusion, the study demonstrated that Ang-(1-7) reduces intestinal inflammation and oxidative injuries associated with acute pancreatitis by activating the Keap1/Nrf2/HO-1 pathway. This suggests that Ang-(1-7) may have therapeutic potential for the treatment of intestinal barrier dysfunction in acute pancreatitis.