Antithrombin ? Attenuates AKI Following Acute Severe Pancreatitis

Background: Antithrombin ?(AT?),the predominant coagulation factor inhibitor,possesses anti-inflammatory properties and exerts renoprotective effects on renal ischemia-reperfusion injury in animal models.However,the AT?'s protective effects on acute kidney injury(AKI)following severe acute pancreatitis(SAP)need to be confirmed.Here,we assessed the protective roles and mechanisms of AT? on AKI following SAP.Methods: Clinical information was extracted for SAP patients in our hospital between July 1,2014 and December 31,2015.The information includes gender,age,AT? activity,and so on.We assessed the association between AT? activities and the incidence of AKI in patients with SAP,and explored therapeutic effects and potential mechanisms of AT? on kidney injury in sodium taurocholate induced SAP rat model.Male Sprague-Dawley rats were divided into four groups,sham + vehicle,SAP + vehicle,SAP + pre-AT?,SAP + post-AT?.The SAP model was established by a standard retrograde infusion of sodium taurocholate solution into the biliary-pancreatic duct.AT? or an equivalent volume of saline was intravenously delivered 30 min before or after sodium taurocholate infusion.All the rats were sacrificed at 18 h following the induction of pancreatitis.Blood samples and kidneys were collected.At the end of the experiment,we evaluated renal dysfunction,renal histological injury,renal inflammation and oxidative stress,and renal cell apoptosis.Human proximal tubular epithelial cells(HK-2)were divided into four groups,control,AT?,TNF?,TNF? + AT?.To explore whether AT? possesses anti-inflammatory properties in vitro,HK-2 cells were pretreated with AT? or vehicle for 6 h before exposed TNF? for consecutive 12 h.Results: Severe acute pancreatitis patients with low AT? activity had a higher incidence of AKI.Moreover,the lowest quartile presented a significantly higher incidence of subsequent AKI.The results demonstrated AT? did not attenuate pancreatic injury,but significantly ameliorate renal dysfunction and renal histological injury.AT? administration reduced blood urea nitrogen(BUN)and serum creatinine(SCr)in SAP rats.Also,AT? inhibited serum tumor necrosis factor ?(TNF?)concentration,as well as the mRNA expression levels of intercellular cell adhesion molecule 1(ICAM-1)and monocyte chemotactic protein 1(MCP-1)in SAP rats.In addition,both intrarenal F4/80-positive cells infiltration and GR-1 positive cells infiltration were mitigated by administration of AT?.Meanwhile,AT? reduced renal malondialdehyde(MDA)levels and increased superoxide dismutase(SOD).AT? decreased caspase-3 expression,and increased anti-apoptosis bcl-2 expression.Furthermore,AT? inhibited TNF?-induced ICAM-1 and MCP-1 expression in HK-2 cells.Conclusion: AT? appears to ameliorate SAP-induced kidney injury by inhibiting inflammation,oxidative stress,and apoptosis.T? supplementation may have a potential prophylactic and therapeutic effect on SAP induced AKI.