Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells
Wünsche, Christin; Koch, Alexander; Goldschmeding, Roel; Schwalm, Stephanie; Meyer Zu Heringdorf, Dagmar; Huwiler, Andrea; Pfeilschifter, Josef
(2015) Biochimica et Biophysica Acta, volume 1851, issue 5, pp. 519 - 526
(Article)
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.
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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.
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Keywords: Cells, Cultured, Connective Tissue Growth Factor, Dose-Response Relationship, Drug, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Mesangial Cells, Mitogen-Activated Protein Kinases, Protein Kinase Inhibitors, RNA Interference, RNA, Messenger, Receptors, Lysosphingolipid, Smad4 Protein, Time Factors, Transfection, Transforming Growth Factor beta2, Up-Regulation, Sphingosine 1-phosphate, S1P receptor, Transforming growth factor β2, Connective tissue growth factor, Human mesangial cell, Kidney
ISSN: 0006-3002
Note: Copyright © 2015 Elsevier B.V. All rights reserved.
(Peer reviewed)