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英超下注韩慧蓉论文被国际权威期刊Hypertension(IF=6.87)接收
作者:  来源:   发布时间:2013-06-26 12:06:38  浏览次数:

A Novel Role of NOD2 in Mediating Ca2+ Signaling:  Evidence from NOD2-regulated Podocyte TRPC6 Channels in Hyperhomocysteinemia

 

Huirong Han1,2, Yupeng Wang1, Xiang Li1, Ping-An Wang1, Xinbing Wei1, Wei Liang3, Guohua Ding3, Xiao Yu4, Chanchan Bao5,Yan Zhang1, Ziying Wang1, and Fan Yi1*

 

1Department of Pharmacology, Shandong University School of Medicine, Jinan, China, 250012

2Department of Pharmacology, Weifang Medical University, Weifang, China, 261053

3Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China, 430060, 4Department of Physiology, Shandong University School of Medicine, Jinan, China, 250012

5The Microscopy Characterization Platform, Shandong University, Jinan, China, 250012

 

 

 

Running title: NOD2 mediates TRPC6 expression and activity

 

 

 

Word count of manuscript:

 

*

Send Correspondence and

Reprint Requests to:   Fan Yi, Ph.D
                   Professor

Department of Pharmacology

Shandong University School of Medicine

                   44#, Wenhua Xi Road,

                   Jinan, Shandong, 250012, P.R. China

Phone : 86-0531-88382616

Fax :   86-0531-88382616

E-mail: fanyi@sdu.edu.cn


 

Abstract

 

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD, 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), one 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 (Hcys)-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 results in podocyte cytoskeleton rearrangement and apoptosis. Moreover, we found that nephrin expression was dependently down-regulated by NOD2 and overexpression of nephrin attenuated Hcys-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 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 ESRD.

Key words: NLR family, Ca2+ mobilization, transient receptor potential channel, homocysteine
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