Wünsche Christin, Koch Alexander, Goldschmeding Roel, Schwalm Stephanie, Meyer Zu Heringdorf Dagmar, Huwiler Andrea, Pfeilschifter Josef
Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Pharmazentrum frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
Biochim Biophys Acta. 2015 May;1851(5):519-26. doi: 10.1016/j.bbalip.2015.01.003. Epub 2015 Jan 17.
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.
众所周知，转化生长因子β2（TGF-β2）可刺激包括人系膜细胞在内的多种细胞类型中促纤维化的结缔组织生长因子（CTGF）的表达。本研究表明，TGF-β2以时间和浓度依赖性方式增强鞘氨醇-1-磷酸受体5（S1P5）的mRNA和蛋白表达。药理学和小干扰RNA方法显示，这种上调是通过经典TGF-β下游效应分子Smad和丝裂原活化蛋白激酶的激活介导的。最值得注意的是，用百日咳毒素抑制Gi以及通过小干扰RNA下调S1P5可阻断TGF-β2刺激的CTGF上调，表明Gi偶联的S1P5是TGF-β2触发人系膜细胞中CTGF表达所必需的。总体而言，这些发现表明TGF-β2依赖性的S1P5上调是TGF-β诱导促纤维化CTGF所必需的。靶向S1P5可能是治疗肾纤维化疾病的一种有吸引力的新方法。
