Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy
Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy
复制标题
DOI：
10.1093/ndt/gfx010
复制
发表时间：
2017-10-01
影响因子：
6.1
通讯作者：
Gruden, Gabriella
中科院分区：
文献类型：
--
作者：
Barutta, Federica;Grimaldi, Serena;Gruden, Gabriella
背景。内源性大麻素系统与糖尿病肾病（DN）的发病机制有关。我们在实验dn中研究了AM6545（一种“外周”限制性大麻素受体1型（CB1R）中性拮抗剂）和AM1241（一种大麻素受体2型（CB2R）激动剂）联合治疗的效果。研究了链脲佐菌素诱导的糖尿病小鼠的肾脏功能和结构、足细胞蛋白以及纤维化和炎症标志物，并分别给药14周、AM6545、AM1241和AM6545-AM1241。在暴露于糖化白蛋白的足细胞中，AM6545或AM1241单独治疗可减少糖尿病诱导的蛋白尿，并防止体内和体外肾素损失。双重治疗优于单一治疗，因为它消除了蛋白尿，炎症，肾小管损伤并显着减少了肾纤维化。趋同抗炎机制解释了双重治疗可消除糖尿病诱导的肾单核细胞浸润和体内M1/M2巨噬细胞失衡，并消除M1巨噬细胞培养基对培养的系膜细胞的纤维化作用。“外周”CB1R阻断在实验性DN中是有益的，并且这种作用被CB2R激活协同放大。
Background. The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.Methods. Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241.Results. Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.Conclusion. 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.