title: The proteoglycan syndecan 4 regulates transient receptor potential canonical 6 channels via RhoA/Rho-associated protein kinase signaling.
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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Frank
authors.initials: F
authors.lastname: Echtermeyer
authors.forename: Florian
authors.initials: F
authors.lastname: Thilo
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.forename: Antje
authors.initials: A
authors.lastname: Schmidt
authors.forename: Ralf
authors.initials: R
authors.lastname: Schülein
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: William J
authors.initials: WJ
authors.lastname: Arendshorst
authors.forename: Martin
authors.initials: M
authors.lastname: Tepel
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D005919:Glomerular Filtration Rate / Q000502:physiology; D007672:Kidney Cortex / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D050199:Podocytes / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D053671:Syndecan-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D020741:rho GTP-Binding Proteins / Q000502:physiology*; D054460:rho-Associated Kinases / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
chemical_list: C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium