Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells

Christin Wünsche; Alexander Koch; Roel Goldschmeding; Stephanie Schwalm; Dagmar Meyer Zu Heringdorf; Andrea Huwiler; Josef Pfeilschifter

doi:10.1016/j.bbalip.2015.01.003

Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells

Christin Wünsche
, Alexander Koch
, Roel Goldschmeding
, Stephanie Schwalm
, Dagmar Meyer Zu Heringdorf
, Andrea Huwiler
, Josef Pfeilschifter

Department of Pathology

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	519-526
Number of pages	8
Journal	Biochimica et Biophysica Acta
Volume	1851
Issue number	5
DOIs	https://doi.org/10.1016/j.bbalip.2015.01.003
Publication status	Published - 2015

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

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10.1016/j.bbalip.2015.01.003

50-mainFinal published version, 1.09 MBLicence: Taverne

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Wünsche, C., Koch, A., Goldschmeding, R., Schwalm, S., Meyer Zu Heringdorf, D., Huwiler, A., & Pfeilschifter, J. (2015). Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells. Biochimica et Biophysica Acta, 1851(5), 519-526. https://doi.org/10.1016/j.bbalip.2015.01.003

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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.",

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",

author = "Christin W{\"u}nsche and Alexander Koch and Roel Goldschmeding and Stephanie Schwalm and \{Meyer Zu Heringdorf\}, Dagmar and Andrea Huwiler and Josef Pfeilschifter",

year = "2015",

doi = "10.1016/j.bbalip.2015.01.003",

language = "English",

volume = "1851",

pages = "519--526",

journal = "Biochimica et Biophysica Acta",

issn = "0006-3002",

number = "5",

}

Wünsche, C, Koch, A, Goldschmeding, R, Schwalm, S, Meyer Zu Heringdorf, D, Huwiler, A & Pfeilschifter, J 2015, 'Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells', Biochimica et Biophysica Acta, vol. 1851, no. 5, pp. 519-526. https://doi.org/10.1016/j.bbalip.2015.01.003

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 et al.
In: Biochimica et Biophysica Acta, Vol. 1851, No. 5, 2015, p. 519-526.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Transforming growth factor β2 (TGF-β2)-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P5) in human mesangial cells

AU - Wünsche, Christin

AU - Koch, Alexander

AU - Goldschmeding, Roel

AU - Schwalm, Stephanie

AU - Meyer Zu Heringdorf, Dagmar

AU - Huwiler, Andrea

AU - Pfeilschifter, Josef

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Cells, Cultured

KW - Connective Tissue Growth Factor

KW - Dose-Response Relationship, Drug

KW - GTP-Binding Protein alpha Subunits, Gi-Go

KW - Humans

KW - Mesangial Cells

KW - Mitogen-Activated Protein Kinases

KW - Protein Kinase Inhibitors

KW - RNA Interference

KW - RNA, Messenger

KW - Receptors, Lysosphingolipid

KW - Smad4 Protein

KW - Time Factors

KW - Transfection

KW - Transforming Growth Factor beta2

KW - Up-Regulation

KW - Sphingosine 1-phosphate

KW - S1P receptor

KW - Transforming growth factor β2

KW - Connective tissue growth factor

KW - Human mesangial cell

KW - Kidney

U2 - 10.1016/j.bbalip.2015.01.003

DO - 10.1016/j.bbalip.2015.01.003

M3 - Article

C2 - 25601519

SN - 0006-3002

VL - 1851

SP - 519

EP - 526

JO - Biochimica et Biophysica Acta

JF - Biochimica et Biophysica Acta

IS - 5

ER -

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

Keywords

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