Wnt/β-catenin Signaling Potential Pathogenic Roles And Its Dignostic Value Of Identification In Lupus Nephritis

SLE(systemic lupus erythematosus,SLE)has been considered as Asia disease,owing to the incidence and severity of this disease are higher in Asian than other populations,Lupus nephritis(LN)is one of the most common complications and one of the leading causes of death in patients with SLE.Therefore,increasing concern and attention have recently been focused in LN research.Previous studies have shown that Wnt/β-catenin signal was involved in several autoimmune diseases,such as rheumatoid arthritis(RA)and SLE,while accumulated evidences demonstrated that Wnt/beta-catenin signaling was able to play regulatory roles in infection and stresses through a mechanism by regulating Toll-like-receptor(TLR)-mediated inflammatory responses.Furthermore,inflammatory factors,such as interleukin-6 are key causes in pathogenesis of lupus nephritis.However the underlying molecular mechanism of lupus nephritis is still far from clear,whether an interaction between Wnt/p-catenin signaling and IL-6 is involved in LN pathogenesis that remains an open question.In the present study,concentrations of Wnt/β-catenin signaling ligand Wnt3a,receptor FZD8 and inhibitor DKK1 in the body fluid(serum and urine)of SLE patients were first ascertained by an ELISA,in order to investigate the relevance of Wnt/β-catenin signaling and LN in clinical settings.Indeed,results from statistical analysis revealed that there was a clinical relevance between the Wnt/β-catenin signaling and and LN SLE.The concentration of DKK1 in serum and urine of SLE patients were higher as compared with those in healthy control group(p<0.0001),despite there was not no statistically significant difference was determined for Wnt3a,FZD8.Interestingly,more abundant DKK1 was detected in the sera and urines of SLE patients with LN,in comparison with non-LN SLE patients(p<0.001).The ROC curve and multivariate analysis further revealed that the specificity and sensitivity of serum DKK1 for LN diagnosis had an area under the curve of 0.783,suggesting that serum DKK1 may be a useful diagnostic biomarker to identify SLE patients with lupus nephritis.In order to explore whether an interaction between IL-6 and Wnt/β-catenin signaling is involved in the pathogenesis of LN in vitro,alterations of Wnt/β-catenin signaling and IL-6 in glomerular mesangial cells in response to immune complex(IC)isolated from sera of LN-SLE patients,IL-6 and/or anti-IL-6 antibody were investigated.The exposure of glomerular mesangial cells to ICs led an inhibition of Wnt/β-catenin signaling activity,along with an increased expression of Wnt signal inhibitory gene GSK3 and Axin1,and a reduced expression nucleus β-catenin,transcription factor TCF-4,and Wnt target gene Cyclin D1.In contrast,the addition of IL-6 to glomerular mesangial cells led to an enhanced Wnt/β-catenin signaling,accompanied by a decreased expression of cell GSK3 and Axin 1,and an increased expression of nuclear β-catenin,TCF-4,and target gene expression of Cyclin D1.These results suggest that ICs of LN-SLE patients inhibit Wnt/β-catenin signaling activity in glomerular mesangial cells,which is in consistent with a higher concentration of Wnt inhibitor DKK1 in sera of LN patients in clinical setting.In conclusion,the results suggest that the concentration of serum DKK1 may be a valuable potential biomarker for identification of LN from SLE in clinic.In addition,serum IC from LN patients and IL-6 showed an oppsited effect in glomerular mesangial cells.ICs could inhibit Wnt/β-catenin signaling in glomerular mesangial cells by mechanism involving in increasing expression of Wnt signal inhibitory gene GSK3 and Axinl,and a reducing expression nucleusβ-catenin,TCF-4,and Cyclin D1,the reduced Wnt/β-catenin signaling might ultimately lead an enhanced inflammatory response.But IL-6,on the other hand,which enhanced Wnt/β-catenin signaling in glomerular mesangial cells.Therefore,results imply an interaction between Wnt/β-catenin signaling and IL-6 may play a pathogenic role in LN,in which Wnt/β-catenin signaling and IL-6 may form a negative feedback loop to regulate immune response of renal cells in response to a stimulation of ICs.This study thus provides an insight for development of LN treatment and lays a foundation for further investigating the pathogenesis of this disease.