The Expression And Significance Of WISP-1 In Renal Fibrosis

Objective: Renal fibrosis is one of the principal causes underlying the progression of chronic kidney diseases(CKD)to end-stage renal disease(ESRD).However,effective therapies with limitted side effects for renal fibrosis are still lacking.Previous studies have found that Wnt1-induced secreted protein-1(WISP-1/CCN4)belonging to CCN family,is involved in lung,heart and liver fibrosis,but its role in renal fibrosis remains unclear.In this study,a series of in vivo,in vitro and clinical experiments were employed to clarify the WISP-1 expression and its clinical significance in renal fibrosis.Methods: Firstly,immunohistochemistry was used to detect the expression and localization of WISP-1 in renal biopsy-proven renal fibrotic-related diseases,including diabetic nephropathy,IgA nephropathy(IgAN)and primary focal segment glomerular sclerosis(FSGS).Then,the level of WISP-1 in the serum of these patients was examined by ELISA.More importantly,the correlation between the WISP-1 in serum with the fibrosis in biopsy tissue was analyzed.Furthermore,the expression of WISP-1 and fibrotic markers including collagen I(Col I),fibronectin(FN)and alpha-smooth muscle actin(a-SMA)was detected in unilateral ureteral obstruction(UUO)mouse model and TGF-β-induced renal fibrosis in rat renal tubular epithelial cells by real-time fluorescence quantitative PCR(qRT-PCR),Western blot(WB)and immunohistochemistry(IHC).Results: The expression of WISP-1 was significantly increased in renal biopsy-proven renal fibrosis patients of IgAN,DN and FSGS,compared to the Minimal change nephropathy(MCD)and normal control groups.And the expression of WISP-1 was mainly localized in renal interstitium.Theconcentration of WISP-1 in IgAN,DN and FSGS was higher than that of MCD and normal control groups(P>0.05).Further,the level of serum WISP-1 in patient with ≥25% fibrosis of IgAN or DN or FSGS were significantly higher than MCD and normal control groups.The expression of WISP-1 was positively correlated with renal fibrosis.In vitro,the expression of WISP-1 and fibrotic markers including Col I、FN、α-SMA was significantly increased following the stimulation of TGF-β1 in rat renal epithelial cells(TEC).Similarly,in vivo,the expression of WISP-1 and fibrotic indexes of Col I、FN and α-SMA was significantly increased in murine renal tissue upon unilateral ureteral obstruction(UUO).Conclusion: The current results show that WISP-1 expression was significantly elevated in renal biopsy specimens and serum of renal fibrosis patients.More importantly,the WISP-1 expression was positively correlated with fibrosis.Also WISP-1 was significantly upregulated in murine kidney upon renal fibrosis induced by UUO and rat renal tubular epithelial cells stimulated by TGF–β1.The results suggest that WISP-1 may be an important factor to promote renal fibrosis and involved in the development of renal fibrosis.