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PMID: 22155451 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Arteriosclerosis, thrombosis, and vascular biology ·Vol. 32 ·No. 2 ·2012-02-00 ·Pages 378-85

Liu Y, Echtermeyer F, Thilo F, Theilmeier G, Schmidt A, Schülein R, Jensen BL, Loddenkemper C, Jankowski V, Marcussen N, Gollasch M, Arendshorst WJ, Tepel M

Abstract

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. 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. 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.

MeSH Terms
Animals Calcium/physiology Cell Membrane/physiology Cells, Cultured Glomerular Filtration Rate/physiology Kidney Cortex/cytology Mice Mice, Knockout Models, Animal Podocytes/cytology,physiology Signal Transduction/physiology Syndecan-4/deficiency,genetics,physiology TRPC Cation Channels/physiology TRPC6 Cation Channel rho GTP-Binding Proteins/physiology rho-Associated Kinases/physiology rhoA GTP-Binding Protein
Chemicals
Sdc4 protein, mouse Syndecan-4 TRPC Cation Channels TRPC6 Cation Channel Trpc6 protein, mouse rho-Associated Kinases RhoA protein, mouse rho GTP-Binding Proteins rhoA GTP-Binding Protein Calcium
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Liu Ying
Odense University Hospital and University of Southern Denmark, Institute for Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research, Winsløwparken 21.3, DK-5000 Odense C, Denmark.
Echtermeyer Frank
Thilo Florian
Theilmeier Gregor
Schmidt Antje
Schülein Ralf
Jensen Boye L
Loddenkemper Christoph
Jankowski Vera
Marcussen Niels
Gollasch Maik
Arendshorst William J
Tepel Martin
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Article Info
Journal
Arteriosclerosis, thrombosis, and vascular biology
Abbr.
Arterioscler Thromb Vasc Biol
ISSN
1524-4636
DOI
10.1161/ATVBAHA.111.241018
Published
2012-02-00
Epub
2011-00-08
Pages
378-85
Language
English
Region
United States
NLM ID
9505803
PMCID
PMC3881556
Subset
IM
Grants
NHLBI NIH HHS · R01 HL002334 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1161/ATVBAHA.111.241018 PMC Full Text View journal details
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