Saracatinib Delays the Progression of Renal Interstitial Fibrosis by Inhibiting the Wnt/β-Catenin Pathway

Key Points In this study, we explored the role and mechanisms underlying the Wnt/ β -catenin signaling pathway in the development of renal interstitial fibrosis Saracatinib effectively inhibits this pathway by binding to Fyn in kidney tissues, blocking the phosphorylation of β -catenin at tyrosine 142. These findings suggest that saracatinib may offer a promising new therapeutic strategy for CKD treatment. Background Renal interstitial fibrosis is a common pathologic feature of CKD and is a critical determinant of disease progression. Recent studies have highlighted the significant role of the Wnt/ β -catenin signaling pathway in the development of renal interstitial fibrosis, but the exact mechanisms remain unclear. Methods Renal tissue samples from CKD patients with renal interstitial fibrosis who underwent renal biopsy at our center between January 2022 and December 2023 were selected for staining. In addition, a rat model of renal interstitial fibrosis was established using unilateral ureteral obstruction (UUO). UUO rats were administered low and high doses of saracatinib via gavage for 2 weeks, followed by examination of changes in relevant indicators. Results In this study, we showed that in the kidney tissues of both CKD patients and rats with renal interstitial fibrosis, there was a marked upregulation of the tyrosine 142 kinase Fyn, which accompanied the excessive activation of the Wnt/ β -catenin pathway. Saracatinib was found to inhibit this pathway by binding to Fyn in kidney tissues, thereby blocking the phosphorylation of β -catenin at tyrosine 142. This inhibition ( 1 ) decreased the serum urea nitrogen and cystatin C levels, along with an increase in serum albumin and total protein concentration, and ( 2 ) alleviated renal interstitial fibrosis in the UUO rat model, resulting in an amelioration of the progression of renal interstitial fibrosis. Conclusions This study suggests that saracatinib may be a novel therapeutic strategy for CKD treatment.