Abstract
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.
Highlights
Liver transplantation is a life-saving procedure for patients with end-stage liver disease, the incidence of which is rising along with the increasing prevalence of its risk factors such as alcoholic and non-alcoholic steatohepatitis, viral infections, and cancer
We demonstrated that hepatic IR is associated with an increase in tissue concentrations of 6-ketoPGF1α (PGI2 ), PGE2, and 13,14-dihydro-PGE1 and with an elevated 6-ketoPGF1α (PGI2 )/TXB2 (TXA2 ) ratio, which was abrogated by pretreatment of IR animals with sitagliptin
We showed that sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2, which seems to be beneficial in the light of the recently reported hepatoprotective effect of the prostaglandin in the course of ischemia and reperfusion
Summary
Liver transplantation is a life-saving procedure for patients with end-stage liver disease, the incidence of which is rising along with the increasing prevalence of its risk factors such as alcoholic and non-alcoholic steatohepatitis, viral infections, and cancer. While procedure frequency is constantly increasing as well, the number of patients requiring transplant exceeds the organ availability. Transplantation is associated with a significant risk of graft rejection, and an ischemia/reperfusion (IR) injury during transplantation is one of the key contributors. A better understanding of its cellular and molecular mechanisms is needed to develop strategies protecting organs during and after transplantation [1,2]. Ischemia causes metabolic imbalance characterized by acidosis and ATP depletion, inducing apoptosis. Unfavorable changes in this phase intensify in the course of reperfusion. Activation of Kupffer cells and infiltration with T lymphocytes during the early phase of reperfusion and accumulation of macrophages and neutrophils during the late phase leads to the release of a plethora of inflammatory and immune mediators and generation of molecule-damaging reactive oxygen and nitrogen species [2]
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