Inhibition Of GSK-3? Attenuates Organ Injure In Rat Kidney Transplantation From Cold Ischemia/Reperfusion Injury

Background: Kidney transplantation is the best alternative therapy for patients with end-stage renal disease.In clinical kidney transplantation,donor kidneys usually undergo two stages of warm ischemia and cold ischemia reperfusion injury(IRI).Cold IRI severely affects the recovery of renal function after kidneyl transplantation and even increases the incidence of acute rejection.Glycogen Synthase Kinase-3?(GSK-3?)plays an indispensable role in the injury and repair of renal tubular epithelial cells.Studies have shown that inhibiting GSK-3? can significantly reduce the activation of nuclear factor-kappa B(NF-?B),reduce the release of inflammatory factors and reduce tissue damage in liver,heart and cerebral IRI.However,the protective effect of GSK3? inhibitor on kidney transplantation has not been reported,and the specific mechanism is not clear.Objective: To investigate the effect of GSK-3?inhibitor TDZD-8 on the activation of NF-?B and oxidative stress during kidney transplantation IRI in rats.Methods: We established rat kidney transplantation model and rat cold IRI model.Each model was randomly divided into following 4 groups:sham operation group(sham group),renal transplantation group(cold IRI group),TDZD-8(5mg/kg)group and TDZD-8(1mg/kg)group,with 6 rats in each group.The changes of p-RelA/p65,p-GSK-3?,GSK-3?and RelA/p65 in two rats were detected by Western-blot and Immunohistochemistry;Changes of TNF-? ? IL-1? ? SOD and MDA in serum were analyzed by Elisa;The pathological changes of the kidneys were observed by HE staining and the renal tubular necrosis score was made;And we used colorimetric assay to detect the changes in serum creatinine and urea nitrogen.Results: When compared with sham operation group,serum creatinine and urea nitrogen,serum TNF-?and IL-1? content,p-RelA/p65,p-GSK-3?expression,NF-?B p65 activity and serum MDA content significantly increased in renal transplantation group and cold IRI group(P<0.01),the activity of GSK-3? and the content of serum SOD significantly decreased(P<0.01),and the pathological damage was aggravated obviously.However,after the intervention of TDZD-8,the levels of serum creatinine and urea nitrogen,renal tubular necrosis score,serum TNF-?and IL-1?contents,p-RelA/p65,p-GSK-3?expression,NF-?B p65 activity and serum MDA level were decreased(P<0.05),the activity of GSK-3?and the content of SOD were increased(P<0.05),and the pathological damage wasreduced.Conclusion: GSK-3?inhibitors can reduce GSK-3?activity,down regulate the phosphorylation of NF-?B,reduce the release of downstream inflammatory factors,lighten renal pathological changes,relieve the severity of oxidative stress,and alleviate IRI in renal transplantation.