Transforming growth factor beta 2 (TGF-beta(2))-induced connective tissue growth factor (CTGF) expression requires sphingosine 1-phosphate receptor 5 (S1P(5)) in human mesangial cells

摘要

Transforming growth factor beta 2 (TGF-beta(2)) 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-beta(2) enhances sphingosine 1-phosphate receptor 5 (S1P(5)) 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-beta downstream effectors, Smad and mitogen-activated protein kinases. Most notably, inhibition of G(i) with pertussis toxin and downregulation of S1P(5) by siRNA block TGF-beta(2)-stimulated upregulation of CTGF, demonstrating that G(i) coupled S1P(5) is necessary for TGF-beta(2)-triggered expression of CTGF in human mesangial cells. Overall, these findings indicate that TGF-beta(2) dependent upregulation of S1P(5) is required for the induction of pro-fibrotic CTGF by TGF-beta. Targeting S1P(5) might be an attractive novel approach to treat renal fibrotic diseases. (C) 2015 Elsevier B.V. All rights reserved.