Cannabinoid receptor 1 is a major mediator of renal fibrosis
Cannabinoid receptor 1 is a major mediator of renal fibrosis
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DOI：
10.1038/ki.2015.63
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发表时间：
2015-07-01
影响因子：
19.6
通讯作者：
Francois, Helene
中科院分区：
文献类型：
--
作者：
Lecru, Lola;Desterke, Christophe;Francois, Helene
继发于肾纤维化的慢性肾脏疾病是公共卫生的负担。有必要探索新的治疗途径，以减少肾纤维化。为了研究这一点，我们使用小鼠单侧输尿管梗阻（UUO）作为肾脏纤维化的实验模型，并通过微阵列分析比较了纤维化肾脏和正常肾脏的基因表达。大麻素受体1 （cannabinoid receptor 1, CB1）是小鼠中表达上调最多的基因之一，其主要内源性CB1配体（2-花生四烯醇甘油）在纤维化肾脏中显著升高。有趣的是，在IgA肾病、糖尿病和急性间质性肾炎患者的肾活检中，CB1表达高度升高。基因和药理学敲除CB1均可显著减少UUO期间的肾纤维化。虽然CB2也参与肾纤维化，但它并没有增强CB1的作用。tgf - β 1刺激后，CB1在肌成纤维细胞（肾纤维化的主要效应细胞）中的表达显著增加。CB1阻断期间肾纤维化的减少可以通过对肌成纤维细胞的直接作用来解释。CB1阻断可降低体外胶原蛋白表达。利莫那班是一种选择性CB1内源性大麻素受体拮抗剂，通过减少单核细胞趋化蛋白-1合成来调节UUO中导致肾纤维化的巨噬细胞浸润。因此，CB1在肌成纤维细胞的激活中起主要作用，可能是治疗慢性肾脏疾病的新靶点。
Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-beta 1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.