Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy.
Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy.
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作者：
Barutta F;Piscitelli F;Pinach S;Bruno G;Gambino R;Rastaldi MP;Salvidio G;Di Marzo V;Cavallo Perin P;Gruden G
大麻素受体2型（CB 2）在慢性退行性疾病中具有保护作用。我们的目的是评估CB 2受体在人类和实验性糖尿病肾病（DN）中的潜在相关性。在晚期DN患者的肾活检、早期实验性糖尿病和培养的足细胞中研究了CB 2表达。内源性大麻素和相关酶的水平在糖尿病小鼠的肾皮质中测量。为了评估CB 2的功能作用，用选择性CB 2激动剂AM 1241治疗链脲佐菌素诱导的糖尿病小鼠14周。在这些动物中，我们研究了白蛋白尿、肾功能、足细胞蛋白（nephrin和闭锁小带-1）的表达以及纤维化（纤连蛋白和转化生长因子-β1）和炎症（单核细胞趋化蛋白-1（MCP-1）、CC趋化因子受体2（CCR 2）和单核细胞标志物）的标志物。在培养的足细胞中评估CB 2信号传导。足细胞在体外和体内均表达CB 2受体。CB 2在晚期DN患者的肾活检中下调，并且在糖尿病小鼠中CB 2配体2-花生四烯酰甘油的肾水平降低，表明CB 2调节受损。在实验性糖尿病中，AM 1241改善了白蛋白尿、足细胞蛋白下调和肾小球单核细胞浸润，而不影响纤维化的早期标志物。此外，AM 1241降低肾皮质和培养足细胞中的CCR 2表达，表明CB 2活化可能干扰MCP-1信号传导的有害作用。CB 2受体由足细胞表达，并且在实验性糖尿病中，CB 2活化改善白蛋白尿和足细胞蛋白损失，表明通过CB 2在DN中的信号传导的保护作用。
The cannabinoid receptor type 2 (CB2) has protective effects in chronic degenerative diseases. Our aim was to assess the potential relevance of the CB2 receptor in both human and experimental diabetic nephropathy (DN). CB2 expression was studied in kidney biopsies from patients with advanced DN, in early experimental diabetes, and in cultured podocytes. Levels of endocannabinoids and related enzymes were measured in the renal cortex from diabetic mice. To assess the functional role of CB2, streptozotocin-induced diabetic mice were treated for 14 weeks with AM1241, a selective CB2 agonist. In these animals, we studied albuminuria, renal function, expression of podocyte proteins (nephrin and zonula occludens-1), and markers of both fibrosis (fibronectin and transforming growth factor-β1) and inflammation (monocyte chemoattractant protein-1 [MCP-1], CC chemokine receptor 2 [CCR2], and monocyte markers). CB2 signaling was assessed in cultured podocytes. Podocytes express the CB2 receptor both in vitro and in vivo. CB2 was downregulated in kidney biopsies from patients with advanced DN, and renal levels of the CB2 ligand 2-arachidonoylglycerol were reduced in diabetic mice, suggesting impaired CB2 regulation. In experimental diabetes, AM1241 ameliorated albuminuria, podocyte protein downregulation, and glomerular monocyte infiltration, without affecting early markers of fibrosis. In addition, AM1241 reduced CCR2 expression in both renal cortex and cultured podocytes, suggesting that CB2 activation may interfere with the deleterious effects of MCP-1 signaling. The CB2 receptor is expressed by podocytes, and in experimental diabetes, CB2 activation ameliorates both albuminuria and podocyte protein loss, suggesting a protective effect of signaling through CB2 in DN.
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影响因子：
7.4
作者：
Mukhopadhyay, Partha;Rajesh, Mohanraj;Pan, Hao;Patel, Vivek;Mukhopadhyay, Bani;Batkai, Sandor;Gao, Bin;Hasko, Gyoergy;Pacher, Pal
通讯作者：
Pacher, Pal
影响因子：
19.6
作者：
Dunn, SR;Qi, ZH;Sharma, K
通讯作者：
Sharma, K
影响因子：
6
作者：
Burt, Davina;Salvidio, Gennaro;Gruden, Gabriella
通讯作者：
Gruden, Gabriella
影响因子：
4.5
作者：
Annuzzi, Giovanni;Piscitelli, Fabiana;Di Marzo, Vincenzo
通讯作者：
Di Marzo, Vincenzo
影响因子：
4.5
作者：
Giunti, Sara;Barutta, Federica;Gruden, Gabriella
通讯作者：
Gruden, Gabriella