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The proteoglycan syndecan 4 regulates transient receptor potential canonical 6 channels via RhoA/Rho-associated protein kinase signaling

Item Type:Article
Title:The proteoglycan syndecan 4 regulates transient receptor potential canonical 6 channels via RhoA/Rho-associated protein kinase signaling
Creators Name:Liu, Y. and Echtermeyer, F. and Thilo, F. and Theilmeier, G. and Schmidt, A. and Schuelein, R. and Jensen, B.L. and Loddenkemper, C. and Jankowski, V. and Marcussen, N. and Gollasch, M. and Arendshorst, W.J. and Tepel, M.
Abstract:OBJECTIVE: Syndecan 4 (Sdc4) modulates signal transduction and regulates activity of protein channels. Sdc4 is essential for the regulation of cellular permeability. We hypothesized that Sdc4 may regulate transient receptor potential canonical 6 (TRPC6) channels, a determinant of glomerular permeability, in a RhoA/Rho-associated protein kinase-dependent manner. METHODS AND RESULTS: Sdc4 knockout (Sdc4(-/-)) mice showed increased glomerular filtration rate and ameliorated albuminuria under baseline conditions and after bovine serum albumin overload (each P<0.05). Using reverse transcription-polymerase chain reaction and immunoblotting, Sdc4(-/-) mice showed reduced TRPC6 mRNA by 79% and TRPC6 protein by 82% (each P<0.05). Sdc4(-/-) mice showed an increased RhoA activity by 87% and increased phosphorylation of ezrin in glomeruli by 48% (each P<0.05). Sdc4 knockdown in cultured podocytes reduced TRPC6 gene expression and reduced the association of TRPC6 with plasma membrane and TRPC6-mediated calcium influx and currents. Sdc4 knockdown inactivated negative regulatory protein Rho GTPase activating protein by 33%, accompanied by a 41% increase in RhoA activity and increased phosphorylation of ezrin (P<0.05). Conversely, overexpression of Sdc4 reduced RhoA activity and increased TRPC6 protein and TRPC6-mediated calcium influx and currents. CONCLUSIONS: Our results establish a previously unknown function of Sdc4 for regulation of TRPC6 channels and support the role of Sdc4 for the regulation of glomerular permeability.
Keywords:Receptors, Signal Transduction, Animals, Mice
Source:Arteriosclerosis Thrombosis and Vascular Biology
ISSN:1079-5642
Publisher:American Heart Association (U.S.A.)
Volume:32
Number:2
Page Range:378-385
Date:February 2012
Official Publication:https://doi.org/10.1161/ATVBAHA.111.241018
PubMed:View item in PubMed

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