科研之友
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摘要
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 beta-catenin. Furthermore, CB2 induced the formation of a beta-arrestin 1/Src/beta-catenin complex, which further triggered the nuclear translocation of beta-catenin and caused fibrotic injury. Incubation with XL-001, an inverse agonist to CB2, or knockdown of beta-arrestin 1 inhibited CB2-triggered activation of beta-catenin and fibrotic injury. Notably, CB2 potentiated Wnt1-induced beta-arrestin 1/beta-catenin activation and augmented the pathogenesis of kidney fibrosis in mice with unilateral ischemia-reperfusion injury or folic acid-induced nephropathy. Knockdown of beta-arrestin 1 inhibited the CB2 agonist AM1241-induced beta-catenin activation and kidney fibrosis. By promoter sequence analysis, putative transcription factor binding sites for T-cell factor/lymphoid enhancer factor were found in the promoter regions of the CB2 gene regardless of the species. Overexpression of beta-catenin induced the binding of T-cell factor/lymphoid enhancer factor-1 to these sites, promoted the expression of CB2, beta-arrestin 1, and the proto-oncogene Src, and triggered their accumulation. Thus, the CB2/beta-catenin pathway appears to create a reciprocal activation feedback loop that plays a central role in the pathogenesis of kidney fibrosis.
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单位南方医科大学
