Objective To investigate the effect of silencing Wnt4 on renal interstitial fibrosis (RIF) and provide atheoretical basis for the treatment of chronic kidney disease. Methods A total of 128 Sprague-Dawley rats were dividedrandomly into four groups of 32 rats each: sham operation, model, negative control and Wnt4 silencing groups. The Wnt4siRNA lentiviral vector was transfected into the silencing group in vivo and divided into four subgroups of eight rats each,at3, 7, 10 and 14 days after transfection. Renal interstitial changes and expression of β-catenin, Wnt4 and α-smooth muscleactin (SMA) were examined by pathology using H&E staining and detected by reverse transcription-polymerase chainreaction. Results The pathological examination showed no renal interstitial changes at the four time points tested in thesham operation group; renal interstitial edema and a small amount of RIF occurred in the UUO group, negative silencing,and silencing groups at 3, 10 and 14 days after modeling. The number of diffuse macrophages and infiltration of lymphocyteswere increased. The negative silencing group showed similar alterations at the UUO group. The silencing group showeddifferent degrees of RIF at the four time points tested. Wnt4 expression was significantly correlated with the expression of β-catenin mRNA ( r =0. 886, P < 0. 001). There was a significant correlation between the mRNA expressions of Wnt4 and α-SMA ( r =0. 930, P < 0. 001). Correlation analysis of mRNA expression in the silencing group after Wnt4 silencing showedthat there was no significant correlation between the mRNA expressions of Wnt4 and β-catenin ( r = 0. 204, P = 0. 263).There was a significant correlation between the mRNA expressions of Wnt4 and α-SMA ( r = 0. 753, P < 0. 001).Conclusion Silencing Wnt4 can significantly inhibit RIF in rats, and may have therapeutic effects.