The Role And Mechanism Of MIF Inhibitor ISO-1 In Severe Acute Pancreatitis-associated Acute Kidney Injury

Background and PurposeAcute pancreatitis(AP)is a common acute abdomen,most patients with mild acute pancreatitis,with a certain limit,about 20%can progress to severe acute pancreatitis,with high mortality.Acute kidney injury(AKI)is one of the most common and important complications of severe acute pancreatitis(SAP).And the mortality rate is significantly higher than SAP patients without AKI.The pathophysiological mechanism of AKI is not clear,and there is no effective treatment.ISO-1,an effective inhibitor targeting MIF,plays a protective role in a variety of diseases,including sepsis,asthma,diffuse axonal injury,Alzheimer’s disease and kidney injury.Previous studies have confirmed that ISO-1 plays a protective role in SAP,and no research has explored the role of ISO-1 in SAP related AKI.This study mainly explored the role and mechanism of ISO-1 in severe acute pancreatitis associated acute kidney injury.Methods1.Mice were randomly divided into 4 treatment groups(6 in each group):CON,SAP,SAP+ISO-1 and ISO-1.HE section was used to observe the injury of pancreas and kidney.2.Serum amylase,lipase,creatinine,uric acid,interleukin(IL)-6 and tumor necrosis factor(TNF)-α were detected by biochemical and enzyme-linked immunosorbent assay(ELISA)kits.3.The expressions of MIF,NLRP3,IL-1β in pancreatic tissue and NLRP3,ASC,caspase-1 and IL-1β in acute kidney tissue were detected by Western blot(WB).4.Kidney NLRP3,ASC,caspase-1 expression and neutrophils infiltration were detected by immunohistochemistry(IHC).5.Kidney MIF,IL-6.TNF-α,IL-1β and IL-18 mRNA were detected by RT-PCR.Results1.In severe acute pancreatitis model,ISO-1 reduced serum amylase,lipase,creatinine,uric acid,IL-6 and TNF-α levels.2.In severe acute pancreatitis model,ISO-1 alleviated the histological changes of pancreas and kidney.3.In severe acute pancreatitis model,ISO-1 decreased the expression of NLRP3 and IL-1β in pancreatic tissue and the protein expression of NLRP3,ASC,caspase-1 and IL-1β in acute kidney tissue.4.In severe acute pancreatitis model,ISO-1 reduced the expression of MIF in pancreatic tissue,the mRNA expression of MIF,IL-6,TNF-α,IL-1β and IL-18 in acute kidney tissue,and the infiltration of MPO positive neutrophils in acute kidney tissue.Conclusion1.ISO-1 alleviates pancreatic and renal tissue injury in severe acute pancreatitis model.2.ISO-1 reduces systemic and kidney inflammatory response in severe acute pancreatitis model.3.ISO-1 has a protective effect against experimental SAP-associated AKI.And the mechanism may be associated with ISO-1 inhibiting NLRP3 inflammasome signaling pathway.