title: Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells.
abstract: Transforming growth factor β2 (TGF-β2) is well known to stimulate the expression of pro-fibrotic connective tissue growth factor (CTGF) in several cell types including human mesangial cells. The present study demonstrates that TGF-β2 enhances sphingosine 1-phosphate receptor 5 (S1P5) mRNA and protein expression in a time and concentration dependent manner. Pharmacological and siRNA approaches reveal that this upregulation is mediated via activation of classical TGF-β downstream effectors, Smad and mitogen-activated protein kinases. Most notably, inhibition of Gi with pertussis toxin and downregulation of S1P5 by siRNA block TGF-β2-stimulated upregulation of CTGF, demonstrating that Gi coupled S1P5 is necessary for TGF-β2-triggered expression of CTGF in human mesangial cells. Overall, these findings indicate that TGF-β2 dependent upregulation of S1P5 is required for the induction of pro-fibrotic CTGF by TGF-β. Targeting S1P5 might be an attractive novel approach to treat renal fibrotic diseases.
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Christin
authors.initials: C
authors.lastname: Wünsche
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. Electronic address: koch@med.uni-frankfurt.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwalm
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Meyer Zu Heringdorf
authors.affiliation: Institute of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C526317:CCN2 protein, human; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D053781:Transforming Growth Factor beta2; D055513:Connective Tissue Growth Factor; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Connective tissue growth factor; Human mesangial cell; Kidney; S1P receptor; Sphingosine 1-phosphate; Transforming growth factor β2