The Effects Of Propofol On Kidney Injury Induced By Liver Cold Ischemia/reperfusion In Rats

Objective: Liver transplantation or other complex liver surgeries inevitably involve in the pathophysiology of hepatic ischemia reperfusion injury,this process not only damages liver cells themselves,but also induces remote organ injury,seriously impacts on patient survival.How to reduce the occurrence of injury after ischemia reperfusion and protect the remote organs is the focus of researches.The study was designed to research the JAK/STAT signaling pathway activition responding to hepatic ischemia reperfusion,meanwhile,we attempted to determine whether propofol modulates this pathway and thus alleviate kidney injury induced by liver cold ischemia reperfusion,revealing potential mechanism of kidney injury induced by liver cold ischemia reperfusion and providing new ideas of prevention and treatment of the remote organ injury after liver ischemia reperfusion.Methods: Healthy male Sprague Dawley rats,8~10 weeks old,weighting 220~250g,were randomly divided into four groups using a random number table(n= 8 each): sham operation group(Sham group);liver cold ischemia/reperfusion model group(I/R group);propofol group(Pro group);JAK2 inhibitor AG490 group(AG490 group).In pro group,propofol at dose of 20 mg· kg-1· h-1 was infused continuously for 30 min via right femoral vein 5 min before reperfusion.In AG490 group,AG490 at dose of 10 mg/kg was applied by intraperitoneal injection 30 min before establishing the model.At 6 h after reperfusion,blood sample was harvested from Inferior vena cava,kidney tissues were obtained,then the rats were sacrificed.The serum concentrations of creatinine(Cr),blood urea nitrogen(BUN)were tested by automatic biochemical analyzer,the serum concentrations of tumor necrosis factor-alpha(TNF-?)and interleukin-6(IL-6)were tested by ELISA kits,and the tissue levels of malondialdehyde(MDA)and superoxide dismutase(SOD)were also detected.The pathologic changes of the renal tissues were observed by HE staining and nephritic cell apoptosis were detected by TUNEL staining.The damage of the renal tubules was scored and apoptotic index(AI)was calculated.Immunohistochemical analyses for changes in expression of Cleaved Caspase-3 in renal cells.The protein levels of p-JAK2,p-STAT1 and p-STAT3 were detected by the western blot analysis.The results were analyzed by SPSS21.0 statistical software,and P < 0.05 has statistical difference.Results: Compared with Sham group,BUN and Cr level gradually increased following reperfusion,indicating renal dysfunction in I/R group(P < 0.05).Meanwhile,liver I/R lead to inflammatory reaction and oxidative stress,the levels of TNF-?,IL-6 and MDA were significantly increased while SOD activity was decreased(P < 0.05).Pathological analyses revealed considerable renal tubular epithelial cell edema,vacuolar degeneration,tubular dilatation,congestion and renal tubular injury score were significantly higher than Sham group.The apoptotic cells increased significantly in I/R group in contrast to the Sham-operated rats,the apoptosis index was higher markedly and the expression of Cleaved Caspase-3 was higer(P < 0.05).With IR rat model,p-JAK2,p-STAT1 and p-STAT3 expression levels gradually increased(P < 0.05)after reperfusion as compared with the Sham group.Compared with I/R group,the animals treated with either propofol or AG490 had an improved renal functional recovery,the levels of BUN,Cr,TNF-?,IL-6 and MDA were significantly decreased while SOD activity was increased(P < 0.05).The histological lesions were attenuated in compared with that of I/R group,accompanied by reduction of the number of TUNEL-positive cells.Immunohistochemical analyses for changes in expression of Cleaved Caspase-3 in renal cells revealed that treatment with propofol or AG490 block the increased Cleaved Caspase-3 expression.Meanwhile,the protein levels of p-JAK2,p-STAT1 and p-STAT3 was down-regulated in Pro group and AG490 group(P < 0.05).Conclusion: Liver cold ischemia reperfusion can lead to kidney injury,and the mechanism is related to inflammation responses,oxidative stress and cell apoptosis.Liver cold ischemia reperfusion can activate the JAK/STAT signaling pathway,inhibiting this pathway can attunate the renal injury after liver cold ischemia reperfusion.Our data showed propofol protects kidney against I/R injury,at least in part,through inhibiting the JAK/STAT signaling pathway activation.