Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy.
Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy.
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DOI：
10.1016/j.freeradbiomed.2009.11.022
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发表时间：
2010-02-01
影响因子：
7.4
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Partha;Rajesh, Mohanraj;Pan, Hao;Patel, Vivek;Mukhopadhyay, Bani;Batkai, Sandor;Gao, Bin;Hasko, Gyoergy;Pacher, Pal
顺铂是一种重要的化疗药物，但其肾毒性限制了其临床应用。增强的炎症反应和氧化/亚硝化应激似乎在顺铂诱导的肾病的发展中起关键作用。用选择性激动剂激活大麻素-2（CB 2）受体在各种疾病模型中发挥抗炎和组织保护作用。我们使用选择性CB 2受体激动剂HU-308和CB 2基因敲除小鼠研究了CB 2受体在顺铂诱导的肾毒性中的作用。顺铂显著增加炎症（白细胞浸润，CXCL 1/2，MCP-1，TNF-α和IL-1 β水平），粘附分子ICAM-1和超氧化物生成酶NOX 2，NOX 4和NOX 1的表达，ROS生成增加，iNOS表达，硝基酪氨酸形成，凋亡和多聚（ADP-核糖）聚合酶依赖性细胞死亡，给药后3天，与明显的组织病理学损伤和肾功能受损（血清尿素氮和肌酸酐水平升高）相关。CB 2激动剂可减轻顺铂诱导的炎症反应、氧化/亚硝化应激和细胞死亡，改善肾功能，而CB 2敲除可增强炎症和组织损伤。因此，内源性大麻素系统通过CB 2受体通过减轻炎症和氧化/亚硝化应激来保护顺铂诱导的肾损伤，选择性CB 2激动剂可能代表一种有前途的新方法来预防这种毁灭性的化疗并发症。
Cisplatin is an important chemotherapeutic agent available; however the nephrotoxicity is limiting its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress appear to play a key role in the development of cisplatin-induced nephropathy. Activation of cannabinoid-2 (CB2) receptors with selective agonists exerts anti-inflammatory and tissue protective effects in various disease models. We have investigated the role of CB2 receptors in cisplatin-induced nephrotoxicity using selective CB2 receptor agonist HU-308 and CB2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNF-α and IL1β levels), expressions of adhesion molecule ICAM-1 and superoxide generating enzymes NOX2, NOX4 and NOX1, enhanced ROS generation, iNOS expression, nitrotyrosine formation, apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days following the administration of the drug. CB2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress and cell death in the kidney and improved renal function, while CB2 knockouts developed enhanced inflammation and tissue injury. Thus, the endocannabinoid system through CB2 receptors protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB2 agonists may represent a promising novel approach to prevent this devastating complication of chemotherapy.
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影响因子：
13.6
作者：
Davis, CA;Nick, HS;Agarwal, A
通讯作者：
Agarwal, A
DOI：
10.1152/ajpheart.00373.2007
发表时间：
2007-08-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Schwaninger, Markus
影响因子：
7.4
作者：
Levrand, Sandra;Vannay-Bouchiche, Christine;Liaudet, Lucas
通讯作者：
Liaudet, Lucas