Referenced in: none

Automatically associated channels: TRP , TRPC , TRPC6

Title: Novel role of NOD2 in mediating Ca2+ signaling: evidence from NOD2-regulated podocyte TRPC6 channels in hyperhomocysteinemia.

Authors: Huirong Han, Yupeng Wang, Xiang Li, Ping-An Wang, Xinbing Wei, Wei Liang, Guohua Ding, Xiao Yu, Chanchan Bao, Yan Zhang, Ziying Wang, Fan Yi

Journal, date & volume: Hypertension, 2013 Sep , 62, 506-11

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23856489

Abstract
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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.