Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy.
Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy.
复制标题
DOI：
10.1038/s41419-022-04786-w
复制
发表时间：
2022-04-12
影响因子：
9
通讯作者：
Cui, Yan
中科院分区：
文献类型：
--
作者：
Kong, Hui;Zhao, Hongran;Chen, Tianran;Song, Yanling;Cui, Yan
视网膜内皮细胞（RECs）是糖尿病引起血管损伤的主要靶细胞。P2X7/NLRP3通路在高血糖和炎症诱导的糖尿病视网膜病变早期通过ATP反馈回路放大炎症，促进rec的炎症反应、焦亡和凋亡中发挥重要作用。3TC是一种核苷类逆转录酶抑制剂，它可以靶向P2X7大孔的形成，对炎症有效。因此，我们的目的是评估3TC对体外高糖（HG）和脂多糖（LPS）处理的视网膜微血管内皮细胞的抗炎作用和潜在的作用机制，以及体内对C57BL/6J雄性链脲霉素诱导糖尿病小鼠视网膜的抗炎作用。比较3tc处理的糖尿病小鼠视网膜炎症小体相关蛋白P2X7和NLRP3的表达以及细胞凋亡。此外，在体外培养的小鼠视网膜内皮细胞中，研究了3TC的抗炎、抗凋亡和抗焦亡作用。HG和LPS联合应用显著增加了IL-6、IL-1β、TNF-α的分泌和ATP水平，而3TC降低了细胞炎症、凋亡和焦亡。抑制P2X7R和NLRP3炎症小体激活可降低NLRP3炎症小体介导的损伤。HG与LPS/BzATP共同作用后，3TC可抑制细胞因子和ATP的释放。我们的研究结果为3TC在糖尿病环境性视网膜损伤（包括凋亡和焦亡）中的作用机制提供了新的见解。
Retinal endothelial cells (RECs) are the primary target cells for diabetes-induced vascular damage. The P2X7/NLRP3 pathway plays an essential role in amplifying inflammation via an ATP feedback loop, promoting the inflammatory response, pyroptosis, and apoptosis of RECs in the early stages of diabetic retinopathy induced by hyperglycemia and inflammation. 3TC, a type of nucleoside reverse transcriptase inhibitor, is effective against inflammation, as it can targeting formation of the P2X7 large pore formation. Hence, our aim was to evaluated the anti-inflammatory effects and potential mechanisms of action of 3TC in vitro in retinal microvascular endothelial cells treated with high-glucose (HG) and lipopolysaccharide (LPS), as well as in vivo in the retinas of C57BL/6J male mice with streptozotocin-induced diabetes. The expression of inflammasome-related proteins P2X7 and NLRP3, and apoptosis in the retinas of 3TC-treated diabetic mice were compared to those of untreated diabetic mice. Furthermore, the anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects of 3TC were evaluated in vitro in cultured mice retinal endothelial cells. Co-application of HG and LPS significantly increased the secretion of IL-6, IL-1β, and TNF-α, and ATP levels, whereas 3TC decreased cell inflammation, apoptosis, and pyroptosis. Inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury. 3TC prevented cytokine and ATP release following co-application of HG and LPS/BzATP. Our findings provide new insights regarding the mechanisms of action of 3TC in diabetic environment-induced retinal injury, including apoptosis and pyroptosis.
登录
查看更多内容
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
影响因子：
4.3
作者：
Jayashree, B.;Bibin, Y. S.;Balasubramanyam, M.
通讯作者：
Balasubramanyam, M.
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1152/ajpendo.00302.2006
发表时间：
2007-03-01
影响因子：
5.1
作者：
Creely, S. J.;McTernan, P. G.;Kumar, S.
通讯作者：
Kumar, S.
糖尿病性视网膜病：神经视网膜对糖尿病代谢环境的丧失。
影响因子：
5.2
作者：
Abcouwer SF;Gardner TW
通讯作者：
Gardner TW