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Accumulating evidence shows that renal fibrosis plays a key role in the development of hypertensive nephropathy (HTN). Therefore, a better understanding of the underlying mechanism of renal fibrosis regulation in HTN would be critical for designing rational strategies for therapeutic interventions. In this study, we revealed that GPR97, a novel identified adhesion G coupled receptor, plays an important role in the regulation of Wnt/β-catenin signaling, which is the crucial driver of renal fibrosis in HTN. First, we identified that the expression of GPR97 correlated with the β-catenin expression in renal biopsy from patients with HTN. Moreover, we found that GPR97 deficiency inhibited Wnt/β-catenin signaling in mice with HTN, as evidenced by the reduction of β-catenin expression and downstream target proteins, including MMP7 and Fibronectin. Mechanistically, we found that GPR97 could directly bind with Wnt1 in cultured tubular cells and TGF-β1 treatment enhanced the binding ability of GPR97 and Wnt1. In addition, the gene silencing of GPR97 could decrease the Wnt1-induced fibrotic phenotype of tubular cells and inflammatory responses, suggesting that the binding of GPR97 and Wnt1 promoted Wnt/β-catenin signaling. Collectively, our studies reveal that GPR97 is a regulator of Wnt/β-catenin signaling in HTN, and targeting GPR97 may be a novel therapeutic strategy for HTN treatment., (© 2024 Federation of American Societies for Experimental Biology.)