The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept
The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept
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DOI：
10.1111/jcmm.14570
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发表时间：
2019-11-01
影响因子：
5.3
通讯作者：
Francois, Helene
中科院分区：
文献类型：
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作者：
Dao, Myriam;Lecru, Lola;Francois, Helene
慢性同种异体移植物功能障碍（CAD），定义为细胞外基质蛋白替代功能性肾组织，仍然是移植物丢失的首要原因。我们研究的目的是探讨大麻素受体 1 (CB1) 在 CAD 过程中的潜在作用。我们回顾性地量化了 26 名接受连续常规肾活检的肾移植患者的 CB1 表达，并将其与肾纤维化相关联。尽管 CB1 在正常肾移植物中表达较低，但在 CAD 期间却呈高表达，尤其是在肾小管细胞中。 CB1 表达在移植后早期即从移植后第 0 天 (D0) 到第 3 个月 (M3) 显着增加（22.5% +/- 15.4% vs 33.4% +/- 13.8%，P < .01），此后保持稳定。 CB1 表达与 M3 肾纤维化相关 (P = .04)。在他克莫司介导的肾小管细胞纤维化的体外模型中，我们发现他克莫司治疗显着诱导 CB1 mRNA 和蛋白表达，同时 col3a1 和 col4a3 上调。给予利莫那班（一种 CB1 拮抗剂）会减弱肾小管细胞的胶原蛋白合成 (P < .05)。总体而言，我们的研究强烈表明大麻素系统参与 CAD 期间纤维化的进展，并表明 CB1 拮抗剂在这种病理学中的治疗潜力。
Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney-transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post-transplant (M3) (22.5% +/- 15.4% vs 33.4% +/- 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus-mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.