Effect Of The JAK2/STAT3 Signaling Pathway On Epithelial Mesenchymal Transition Of The Peritoneum In Uremic Peritoneal Dialysis Rats With 5/6 Nephrectomy

ObjectiveThe latest study found that peritoneal dialysis(PD)treatment eventually raised the incidence rate of peritoneal fibrosis and ultrafiltration failure(UFF).Due to the bad biocompatibility of peritoneal dialysis fluids,such as high glucose concentration,low pH,glucose degradation products(GDPs)etc.The mechanism of peritoneal fibrosis has not been fully understood so far.However,the large accumulation of activated fibroblasts in the peritoneum played an important role in peritoneal fibrosis,and the studies have proved that the myofibroblasts were mainly transformed from peritoneal mesothelial cells by epithelial mesenchymal transdifferentiation(EMT).The purpose of this study was to observe the effects of high glucose peritoneal dialysis fluid on the pathology and function of rat peritoneum and the change of IL-6 concentration in rats,activation of JAK2/STAT3 signaling pathway and alteration of EMT in rat peritoneal tissue by constructing a 5/6 nephrectomy peritoneal dialysis(PD)model.After the JAK2/STAT3 signaling pathway was blocked by the STAT3 inhibitor S3I-201,the changes of pathological,function and EMT in the peritoneum,and IL-6 concentration in the rats were observed.Finally,to investigate whether the IL-6 and JAK2/STAT3 signaling pathway were involved in the peritoneal fibrosis of uremic peritoneal dialysis(PD)rats.MethodsSprague-Dawley(SD)rats were randomly separated into six groups: A: normal control group,B: sham operated control group,C: uremic group,D: peritoneal dialysis group,E: S3I-201 control group,F: S3I-201 group(all n=8).The rats of C,D,E and F group had 5/6 nephrectomy surgery to generate the uremic model.The D,E and F group rats received daily infusion of 4.25% glucose-based peritoneal dialysate fluid(PDF)(3 ml/100 g)from peritoneal dialysis catheters for 28 days.F group rats were injected with STAT3 inhibitor S3I-201(2.5 mg/Kg)solutions from the catheter once every two days;the same dose of the solvent of S3I-201 was simultaneously given to the E group rats.After 28 days of dialysis,evaluate peritoneal function,pathologic changes,and microvessel density(MVD).Detection creatinine,urea nitrogen and interleukin-6(IL-6)concentration of blood and dialysate,and protein and mRNA levels of phospho-JAK2(p-JAK2),phospho-STAT3(p-STAT3),E-cadherin,?-smooth muscle actin(?-SMA)and vascular endothelial growth factor(VEGF)of peritoneum.Results1 Compared with the normal control group,the ratio of peritoneal dialysis fluid and serum creatinine(D/Pcr),peritoneal thickness and MVD,IL-6 concentration in rats of uremic group were increased significantly,while the ultrafiltration volume(UF)were decreased significantly(all P<0.05).Although the protein expression of E-cadherin was decreased,while the protein expression of?-SMA,VEGF,p-JAK2 and p-STAT3 protein were increased,but there were no significant difference between the normal control group and uremic group.2 Although uremia could cause certain deterioration of peritoneal function and pathology in rats,peritoneal dialysis made further deterioration of peritoneal function and pathology.Compared with the normal control group,in the peritoneal dialysis group,D/Pcr,peritoneal thickness and MVD,IL-6 concentration,expression of ?-SMA,VEGF,p-JAK2,and p-STAT3 in rats were increased further,and UF and expression of E-cadherin decreased(all P<0.05).3 There was no statistical difference between the S3I-201 control group and the PD group of each index(all P> 0.05).4 Compared with the S3I-201 control group,the rats treated with S3I-201 showed better peritoneal function.S3I-201 reduced peritoneal thickness,MVD,the concentration of IL-6 in rats and the expression of ?-SMA,VEGF,p-JAK2 and p-STAT3 while enhancing the expression of E-cadherin(all P<0.05).ConclusionsAfter the inhibition of STAT3,peritoneal thickness,angiogenesis and concentration of IL-6 of PD rats declined and peritoneal function improved,and the EMT level was attenuated.The JAK2/STAT3 signaling pathway may be involved in the process of EMT of peritoneum in uremic peritoneal dialysis rats by regulating the expression of IL-6.