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Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.

Abstract：

:The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood. Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury. In vitro, forced expression of CB2 or treatment with a CB2 agonist was sufficient to trigger matrix gene expression, whereas knockdown of CB2 by siRNA abolished transforming growth factor-β1-induced signaling and fibrogenic responses in kidney tubular cells. CB2 also mediated fibroblasts and macrophage activation in vitro. Mice with genetic ablation of CB2 were protected against kidney injury after ureteral obstruction, validating a pathogenic role of CB2 in renal fibrosis in vivo. By using in silico screening and medicinal chemistry modifications, we discovered a novel compound, XL-001, that bound to CB2 with high affinity and selectivity and acted as an inverse agonist. Incubation with XL-001 inhibited in a dose-dependent fashion the fibrogenic response induced by CB2 overexpression, CB2 agonist or transforming growth factor-β1. In vivo, intraperitoneal injections of XL-001 ameliorated kidney injury, fibrosis and inflammation in both the obstruction and ischemia/reperfusion models. Delayed administration of XL-001 was also effective in ameliorating kidney fibrosis and inflammation. Thus, CB2 is a pathogenic mediator in kidney fibrosis and targeted inhibition with the novel inverse agonist XL-001 may provide a strategy in the fight against fibrotic kidney diseases.

journal_name

Kidney Int

journal_title

Kidney international

authors

Zhou L,Zhou S,Yang P,Tian Y,Feng Z,Xie XQ,Liu Y

doi

10.1016/j.kint.2018.05.023

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

756-772

issue

4

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(18)30397-1

journal_volume

94

pub_type

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