Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy

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.

Sophocarpine attenuates septic liver injury through suppression of the NLRP3 inflammasome via autophagy‑mediated degradation

“…The authors confirm that the animals received humane care and that all animal experiments were performed in accordance with the relevant guidelines and regulations (4). The CLP mouse model was established as previously reported (16). Mice were administered with sophocarpine through oral gavage for 3 days.…”

“…The mice were sacrificed on day 6 and blood and liver samples were obtained. Bafilomycin A (10 mg/kg) ( 16 ) or MG-132 (10 µg/kg; MedChemExpress), according to previously proposed dosages ( 17 ), were injected intraperitoneally 2 h before the CLP procedure (these inhibitor is administered at the operation day). After the CLP procedure, mice were administered sophocarpine for the following 3 days.…”

HIPK2 Is Required for Midbody Remnant Removal Through Autophagy-Mediated Degradation

“…Autophagy is the main specific degradation mechanism for MBR removal (Pohl and Jentsch, 2009;Kuo et al, 2011;Isakson et al, 2013). Recently, exogenous expression of HIPK2 in primary mouse hepatocytes has been shown to stimulate autophagy (Jiang et al, 2018). Thus, we asked whether HIPK2 might have a role in mediating MBR autophagic degradation.…”

“…Each of these steps can be dynamically regulated via a complex network of autophagy-relevant proteins and by posttranslational modifiers including kinases (Stork et al, 2012). It has been suggested that HIPK2 overexpression promotes phagophore expansion and increases mature autophagosome formation in liver sepsis (Jiang et al, 2018). In Caenorhabditis elegans, the HIPK-family orthologous HPK-1 is required for inducing autophagosome formation and autophagy gene expression in response to dietary restriction or TORC1 inactivation (Das et al, 2017).…”

Exosomal miR-19a from adipose-derived stem cells suppresses differentiation of corneal keratocytes into myofibroblasts

“…Moreover, deposition of extracellular matrix and decreased crystallin protein expression by the keratocytes causes scar formation and reduces corneal transparency [8]. Therefore, effective methods are necessary to inhibit Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that is primarily located in the nucleus of eukaryotic cells [23]. HIPK2 is a pro-fibrotic gene that plays an important role in kidney fibrosis [24].…”