Novel Role of NOD2 in Mediating Ca2+ Signaling: Evidence From NOD2-Regulated Podocyte TRPC6 Channels in Hyperhomocysteinemia
Novel Role of NOD2 in Mediating Ca2+ Signaling: Evidence From NOD2-Regulated Podocyte TRPC6 Channels in Hyperhomocysteinemia
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NOD2 在介导 Ca2 信号传导中的新作用：高同型半胱氨酸血症中 NOD2 调节的足细胞 TRPC6 通道的证据
DOI：
10.1161/hypertensionaha.113.01638
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发表时间：
2013-09-01
期刊：
影响因子：
8.3
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Han, Huirong;Wang, Yupeng;Yi, Fan
虽然高同型半胱氨酸血症（hHcys）已被认为是终末期肾病进展和与终末期肾病相关的心血管并发症发展的重要独立危险因素，但触发hHcys致病作用的机制尚未完全了解。本研究旨在探讨细胞内天然免疫介质NOD2在hHcys肾小球硬化形成中的作用。我们的研究结果表明，NOD2缺乏减轻hHcys小鼠的肾损伤。我们进一步发现NOD2在介导Ca2+信号中的新作用，并发现同型半胱氨酸诱导的NOD2表达增强瞬时受体电位阳离子通道6（TRPC 6）表达和TRPC 6介导的钙内流和电流，导致细胞内Ca2+释放，最终导致足细胞骨架重排和凋亡。此外，我们发现nephrin的表达下调依赖于NOD2，和nephrin过表达衰减同型半胱氨酸诱导的TRPC 6在足细胞的表达。这些结果增加了支持nephrin在介导NOD2诱导的hHcys中TRPC 6表达中的重要作用的证据。总之，我们的研究结果首次建立了一个以前未知的功能NOD2的TRPC 6通道的调节，表明TRPC 6依赖的Ca2+信号转导是关键的信号转导途径之一，连接先天免疫介质NOD2足细胞损伤。药理学靶向NOD2信号通路在多个水平可能有助于设计一种新的方法来开发治疗策略，用于治疗hHcys相关的终末期肾病。
Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and in the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering the pathogenic actions of hHcys are not yet fully understood. The present study was designed to investigate the contribution of nucleotide-binding oligomerization domain containing 2 (NOD2), an intracellular innate immunity mediator, to the development of glomerulosclerosis in hHcys. Our results showed that NOD2 deficiency ameliorated renal injury in mice with hHcys. We further discovered the novel role of NOD2 in mediating Ca2+ signaling and found that homocysteine-induced NOD2 expression enhanced transient receptor potential cation channel 6 (TRPC6) expression and TRPC6-mediated calcium influx and currents, leading to intracellular Ca2+ release, ultimately resulting in podocyte cytoskeleton rearrangement and apoptosis. Moreover, we found that nephrin expression was downregulated dependently by NOD2, and overexpression of nephrin attenuated homocysteine-induced TRPC6 expression in podocytes. The results add evidence to support the essential role of nephrin in mediating NOD2-induced TRPC6 expression in hHcys. In conclusion, our results for the first time establish a previously unknown function of NOD2 for the regulation of TRPC6 channels, suggesting that TRPC6-dependent Ca2+ signaling is one of the critical signal transduction pathways that links innate immunity mediator NOD2 to podocyte injury. Pharmacological targeting of NOD2 signaling pathways at multiple levels may help design a new approach to develop therapeutic strategies for treatment of hHcys-associated end-stage renal disease.