Department of Medical Sciences, University of Turin, Turin, Italy.
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Br J Pharmacol. 2018 Dec;175(23):4371-4385. doi: 10.1111/bph.14495. Epub 2018 Nov 6.
The endocannabinoid (EC) system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effects of peripheral blockade of the cannabinoid CB receptor as an add-on treatment to ACE-inhibition in type 1 diabetic mice (DM) with established albuminuria.
Renal functional parameters (albumin excretion rate, creatinine clearance), tubular injury, renal structure, both EC and CB receptor levels and markers of podocyte dysfunction, fibrosis and inflammation were studied in streptozotocin-induced DM treated for 14 weeks with vehicle, the ACE-inhibitor perindopril (2 mg·kg ·day ), peripherally-restricted CB receptor antagonist AM6545 (10 mg·kg ·day ) or both. Treatments began at 8 weeks after diabetes onset, when early DN is established.
CB receptors were overexpressed in DM and neither perindopril nor AM6545 altered this effect, while both drugs abolished diabetes-induced overexpression of angiotensin AT receptors. Single treatment with either AM6545 or perindopril significantly reduced progression of albuminuria, down-regulation of nephrin and podocin, inflammation and expression of markers of fibrosis. However, reversal of albuminuria was only observed in mice administered both treatments. The ability of the combination therapy to completely abolish slit diaphragm protein loss, monocyte infiltration, overexpression of inflammatory markers and favour macrophage polarization towards an M2 phenotype may explain this greater efficacy. In vitro experiments confirmed that CB receptor activation directly inhibits retinoic acid-induced nephrin expression in podocytes and IL-4-induced M2 polarization in macrophages.
Peripheral CB receptor blockade used as add-on treatment to ACE-inhibition reverses albuminuria, nephrin loss and inflammation in DM.
内源性大麻素（EC）系统参与了糖尿病肾病（DN）的发病机制。我们研究了外周大麻素 CB 受体阻断作为附加治疗在患有白蛋白尿的 1 型糖尿病小鼠（DM）中对 ACE 抑制的影响。
研究了肾脏功能参数（白蛋白排泄率、肌酐清除率）、肾小管损伤、肾脏结构、EC 和 CB 受体水平以及足细胞功能障碍、纤维化和炎症的标志物，这些标志物在链脲佐菌素诱导的 DM 中进行了研究，用 vehicle、ACE 抑制剂培哚普利（2mg·kg·day）、外周限制 CB 受体拮抗剂 AM6545（10mg·kg·day）或两者联合治疗 14 周。治疗从糖尿病发病后 8 周开始，此时早期 DN 已经建立。
CB 受体在 DM 中过度表达，培哚普利和 AM6545 都没有改变这种效应，而这两种药物都消除了糖尿病诱导的血管紧张素 AT 受体过度表达。单独使用 AM6545 或培哚普利均可显著降低白蛋白尿的进展、下调足细胞中的 Nephrin 和 Podocin、炎症和纤维化标志物的表达。然而，只有在给予两种治疗的小鼠中才观察到白蛋白尿的逆转。联合治疗完全消除裂孔隔膜蛋白丢失、单核细胞浸润、炎症标志物过度表达并促进巨噬细胞向 M2 表型极化的能力可能解释了这种更大的疗效。体外实验证实，CB 受体激活可直接抑制视黄酸诱导的足细胞中 Nephrin 的表达和 IL-4 诱导的巨噬细胞向 M2 极化。
作为 ACE 抑制的附加治疗，外周 CB 受体阻断可逆转 DM 中的白蛋白尿、Nephrin 丢失和炎症。
