Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Molecules. 2021 Feb 6;26(4):866. doi: 10.3390/molecules26040866.
The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.
大麻素受体在肾病中的作用越来越受到关注。本研究探讨了两种中性 CB1 受体拮抗剂 AM6545 和 AM4113 对代谢综合征（MetS）相关肾病的影响。MetS 通过高果糖高盐喂养 12 周诱导大鼠。在研究的最后 4 周给予 AM6545（外周沉默拮抗剂）和 AM4113（中枢中性拮抗剂）。研究结束时，收集血液和尿液样本进行生化分析，同时切除肾脏进行组织病理学检查和转化生长因子β1（TGFβ1）测量。MetS 与肾功能恶化有关，表现为蛋白尿和白蛋白排泄率升高。两种化合物均能抑制蛋白尿和白蛋白排泄率的升高，而对肌酐清除率和血压无影响。此外，AM6545 和 AM4113 缓解了不同肾脏结构中观察到的肿胀和炎症细胞浸润。此外，AM6545 和 AM4113 缓解了 MetS 大鼠肾脏结构中观察到的组织病理学改变。MetS 与尿酸尿增加十倍有关，而两种化合物均阻止了这种增加。此外，AM6545 和 AM4113 完全阻止了 MetS 动物中胶原沉积和 TGFβ1 表达的升高。总之，AM6545 和 AM4113 通过外周作用干扰 TGFβ1 介导的肾脏炎症和纤维化，具有肾脏保护作用。
