Cannabinoid receptor type 2 promotes kidney fibrosis through orchestrating β-catenin signaling

pubmed: wnt1 2021-03-01

Kidney Int. 2021 Feb;99(2):364-381. doi: 10.1016/j.kint.2020.09.025. Epub 2020 Nov 2.

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 further triggered the nuclear translocation of β-catenin and caused fibrotic injury. Incubation with XL-001, an inverse agonist to CB2, or knockdown of β-arrestin 1 inhibited CB2-triggered activation of β-catenin and fibrotic injury. Notably, CB2 potentiated Wnt1-induced β-arrestin 1/β-catenin activation and augmented the pathogenesis of kidney fibrosis in mice with unilateral ischemia-reperfusion injury or folic acid-induced nephropathy. Knockdown of β-arrestin 1 inhibited the CB2 agonist AM1241-induced β-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 β-catenin induced the binding of T-cell factor/lymphoid enhancer factor-1 to these sites, promoted the expression of CB2, β-arrestin 1, and the proto-oncogene Src, and triggered their accumulation. Thus, the CB2/β-catenin pathway appears to create a reciprocal activation feedback loop that plays a central role in the pathogenesis of kidney fibrosis.

PMID:33152447 | DOI:10.1016/j.kint.2020.09.025