Niclosamide Attenuates Inflammatory Response And Renal Injury In Septic Rats By Inhibiting Notch Signaling Pathway

Objective:The aim of this study was to investigate the effects of niclosamide(NIC)on systemic inflammatory response and renal injury in a rat model of lipopolysaccharide(LPS)-induced sepsis.Methods: Thirty-three SPF-grade SD male rats were divided into three groups using the random number method: 6 in the CONTROL group:intraperitoneal injection of DMSO + corn oil;18 in the LPS group: intraperitoneal injection of DMSO + corn oil + LPS;9 in the LPS + NIC group: intraperitoneal injection of DMSO + corn oil + LPS + NIC.the cumulative survival rate of septic rats was observed for 24 h.And blood was taken from the abdominal aorta and executed 24 hours after modeling,and related tissues such as kidney were collected,and the levels of inflammatory indexes(IL-6,TNF-α)and kidney injury markers(KIM-1,Scr)in serum were detected by enzyme-linked immunosorbent assay(ELISA),and the pathological changes of kidney tissues were observed by hematoxylin-eosin staining(HE),and Western blotting(WB)to detect the protein levels of IL-6,TNF-α,NICD and Hes1 in kidney tissues.Results:(1)24-hour rat survival and death: 6 rats survived and 0 died in the CONTROL group,8 rats survived and 10 rats died in the LPS group,and 8 rats survived and 1 rat died in the LPS+NIC group.(2)ELISA: In terms of inflammation indexes,the serum levels of IL-6 and TNF-α in rats in the LPS group were increased by about 3.4 and3.1-fold,respectively,compared with the CONTROL group(P< 0.001);the serum levels of IL-6 and TNF-α in rats in the LPS+NIC group were decreased by about 51% and 62%,respectively,compared with the LPS group(P < 0.001).In terms of renal injury indexes,the serum levels of KIM-1 and Scr in rats in the LPS group were increased by 3.8-fold and 5.4-fold,respectively,compared with the CONTROL group(P< 0.01);the serum levels of KIM-1 and Scr in rats in the LPS+NIC group were decreased by about 41% and28%,respectively,compared with the LPS group(P< 0.05).(3)HE staining: compared with the CONTROL group,the kidney tissues of rats in the LPS group showed a large number of inflammatory cell infiltration,glomerular consolidation,tubular structural damage,brush border detachment and basement membrane rupture;compared with the LPS group,the kidney tissues of rats in the LPS+NIC group showed significantly less inflammatory cell infiltration,glomerular consolidation,tubular structural damage,brush border detachment and basement membrane rupture.(4)WB: Compared with the CONTROL group,the contents of IL-6,TNF-α,NICD and Hes1 in the kidney tissues of rats in the LPS group were increased by about 1.6,1.5,1.5 and 1.7 times(P< 0.05);compared with the LPS group,the contents of IL-6,TNF-α,NICD and Hes1 in the kidney tissues of rats in the LPS+NIC group were decreased by about 36%,37%,35%and 35%(P< 0.05).(2)ELISA: On inflammation indexes,serum levels of IL-6 and TNF-αin the LPS group were increased by about 3.4 and 3.1 times,respectively,compared with the CONTROL group(P< 0.001);serum levels of IL-6 and TNF-α in the LPS+NIC group were decreased by about 51% and 62%,respectively,compared with the LPS group(P < 0.001).In terms of renal injury indexes,serum levels of KIM-1 and Scr in the LPS group were increased by 3.8-fold and 5.4-fold,respectively,compared with the CONTROL group(P< 0.01);serum levels of KIM-1 and Scr in the LPS+NIC group were decreased by about 41% and 28%,respectively,compared with the LPS group(P< 0.05).(3)HE staining: compared with the CONTROL group,all the kidney tissues in the LPS group showed a large number of inflammatory cell infiltration,glomerular consolidation,tubular structural destruction,and brush border detachment;compared with the LPS group,the kidney tissues in the LPS+NIC group showed significantly less inflammatory cell infiltration,glomerular consolidation,tubular structural destruction,and brush border detachment.(4)WB:Compared with the CONTROL group,the LPS group: the levels of IL-6,TNF-α,NICD and Hes1 in renal tissues were elevated by approximately 1.6,1.5,1.5 and 1.7-fold(P< 0.05);compared with the LPS group,the levels of IL-6,TNF-α,NICD and Hes1 in renal tissues were decreased by approximately 36%,37%,35% and35%(P< 0.05).Conclusion:Niclosamide intervention can reduce systemic inflammatory response and renal injury induced by lipopolysaccharide in septic rats.