title: Novel role of NOD2 in mediating Ca2+ signaling: evidence from NOD2-regulated podocyte TRPC6 channels in hyperhomocysteinemia.
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.
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, 44# Wenhua Xi Rd, Jinan, Shandong 250012, China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Han
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Ping-An
authors.initials: PA
authors.lastname: Wang
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.forename: Guohua
authors.initials: G
authors.lastname: Ding
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Chanchan
authors.initials: C
authors.lastname: Bao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ziying
authors.initials: Z
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D003599:Cytoskeleton; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D008565:Membrane Proteins; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; C113267:nephrin
keywords: NLR family; calcium signaling; homocysteine; transient receptor potential channel