HIPK2 adenovirus

Sepsis is the leading cause of death in intensive care units worldwide. Autophagy has recently been shown to protect against sepsis-induced liver injury. Here, researchers investigated the role of homeodomain-interacting protein kinase 2 (HIPK2) in the molecular mechanisms of sepsis-induced liver injury. HIPK2 expression was reduced in sepsis-induced liver injury, while HIPK2 overexpression increased the survival rate of mice and improved cecal ligation and puncture (CLP)-induced liver injury by reducing serum and hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in septic mice. HIPK2 overexpression significantly reduced the release of CLP-induced inflammatory cytokines into serum and attenuated oxidative stress-related indicators in mice with CLP-induced liver injury, while HIPK2 knockdown produced the opposite results, indicating that HIPK2 is a negative regulator of sepsis. In addition, HIPK2 overexpression inhibited lipopolysaccharide (LPS)-induced apoptosis in primary hepatocytes, increased autophagic flux, and restored the formation of autophagosomes and autolysosomes in CLP-induced mouse livers by inhibiting calpain signaling. More importantly, HIPK2 overexpression reduced the elevated cytosolic Ca2+ concentration in LPS-treated primary hepatocytes by interacting with calpain 1 and calmodulin. In conclusion, HIPK2 overexpression may improve sepsis-induced liver injury by restoring autophagy and may therefore be a promising target for the clinical treatment of sepsis.

Here, the researchers overexpressed HIPK2 to investigate possible liver changes. Ad-HIPK2 and Ad-shHIPK2 adenoviruses successfully altered HIPK2 expression in the liver, but not in other organs (Figure 1a, b). Based on this premise, the 16-day survival rate was 16.7% in the CLP-induced sepsis group, 60.0% in the Ad-HIPK2-injected sepsis group, 6.67% in the Ad-shHIPK2-injected sepsis group (Figure 1c), and 100% in the control group. The 16-day survival rate of the Ad-HIPK2-treated sepsis group was improved compared with the sepsis group (Figure 1c), indicating that pretreatment of mice with Ad-HIPK2 before CLP significantly reduced mortality compared with CLP-induced sepsis animals. However, knocking down the HIPK2 gene by Ad-shHIPK2 may increase the lethality of mice. In addition, the levels of AST, ALT, and ALP in septic mice were higher than those in the sham operation group (normal group), and Ad-HIPK2 significantly reduced the levels of AST, ALT, and ALP in the serum and liver of septic mice (Figure 1d-i). In contrast, knockdown of the HIPK2 gene (Ad-shHIPK2) increased the levels of AST, ALT, and ALP in the serum and liver of septic mice (Figure 1d-i). These data suggest that HIPK2 plays a protective role in sepsis and its associated acute liver injury, which may be related to its reduction of liver ALT, AST, and ALP content.

Figure 1. Effects of HIPK2 on sepsis-induced lethality and production of liver injury-related factors in CLP-induced mice. (Jiang Z, et al., 2018)