Abstract The endocannabinoid system has multiple effects. Through interacting with cannabinoid receptor type 1 and type 2, this system can greatly affect disease progression. Previously, we showed that activated cannabinoid receptor type 2 (CB2) mediated kidney fibrosis. However, the underlying mechanisms remain underdetermined. Here, we report that CB2 was upregulated predominantly in kidney tubular epithelial cells in unilateral urinary obstruction and ischemia-reperfusion injury models in mice, and in patients with a variety of kidney diseases. CB2 expression was closely correlated with the progression of kidney fibrosis and accompanied by the activation of β-catenin. Furthermore, CB2 induced the formation of a β-arrestin 1/Src/β-catenin complex, which...