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Abstract
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, we investigated the roles of homeodomain-interacting protein kinase 2 (HIPK2) in the molecular mechanism of sepsis-induced liver injury. HIPK2 expression was reduced in sepsis-induced liver injury, and HIPK2 overexpression increased the survival rate and improved caecal ligation and puncture (CLP)-induced liver injury by reducing serum and liver aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) levels in mice with sepsis. HIPK2 overexpression significantly decreased CLP-induced release of inflammatory cytokines into the serum and attenuated oxidative stress-associated indicators in mice with CLP-induced liver injury, whereas HIPK2 knockdown produced the opposite results, suggesting that HIPK2 is a negative regulator of sepsis. Furthermore, HIPK2 overexpression inhibited lipopolysaccharide (LPS)-induced apoptosis of primary hepatocytes, increased the autophagic flux, and restored both autophagosome and autolysosome formation in the livers of CLP-induced mice by suppressing calpain signalling. Importantly, HIPK2 overexpression reduced the elevated cytosolic Ca2+ concentration in LPS-treated primary hepatocytes by interacting with calpain 1 and calmodulin. Finally, several anti-inflammatory drugs, including resveratrol, aspirin, vitamin E and ursolic acid, significantly increased the levels of the HIPK2 mRNA and protein by modulating promoter activity and the 3′-UTR stability of the HIPK2 gene. In conclusion, HIPK2 overexpression may improve sepsis-induced liver injury by restoring autophagy and thus might be a promising target for the clinical treatment of sepsis.
Highlights
Sepsis has been considered the leading cause of death in intensive care units worldwide[1]
Recent studies using a caecal ligation and puncture model (CLP) to induce sepsis have observed a significant increase in autophagy in the mouse liver that was identical to clinical patients[19,20], and the activation of autophagy may be enhanced by genipin and growth arrest and DNA damage inducible protein 34 (GADD34), which exert protective effects against sepsis[13,14]
homeodomain-interacting protein kinase 2 (HIPK2) functionally interacts with NRF234, a transcription factor involved in protecting the liver and autophagy[35,36,37,38,39,40]
Summary
Sepsis has been considered the leading cause of death in intensive care units worldwide[1]. Jiang et al Cell Death and Disease (2018)9:847 sepsis-induced liver dysfunction is induced by multiple pathogenic factors[6], including lipopolysaccharide (LPS), inflammatory factors, or pathogens[5,7,8,9]. Upregulation of autophagy attenuates the inflammatory response and improves the survival rate by reducing organ dysfunction[16], whereas inhibition of autophagy has been reported to result in increased mortality by exacerbating injury induced by multiple factors and depleting immune cells in patients with sepsis[17,18]. Recent studies using a caecal ligation and puncture model (CLP) to induce sepsis have observed a significant increase in autophagy in the mouse liver that was identical to clinical patients[19,20], and the activation of autophagy may be enhanced by genipin and growth arrest and DNA damage inducible protein 34
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