Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells.
Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells.
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DOI：
10.1007/s11302-017-9571-6
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发表时间：
2017-12
影响因子：
3.5
通讯作者：
Di Iorio P
中科院分区：
文献类型：
--
作者：
Zuccarini M;Giuliani P;Buccella S;Di Liberto V;Mudò G;Belluardo N;Carluccio M;Rossini M;Condorelli DF;Rathbone MP;Caciagli F;Ciccarelli R;Di Iorio P
上皮向间充质转化（EMT）发生在胚胎发生过程中或在缺氧、损伤、慢性炎症或组织纤维化等病理条件下。在肾小管上皮细胞（MDCK）中，TGF-β1分别通过降低或增加上皮或间充质标志物表达诱导EMT。在这项研究中，我们证实了cAMP类似物，8-CPT-cAMP或N6-Ph-cAMP，抑制TGF-β1驱动的间充质标记物ZEB-1、Slug、Fibronectin和α-SMA的过表达。此外，我们发现A1、A2A、P2Y1、P2Y11和P2X7嘌呤受体激动剂通过参与PKA和/或MAPK/ERK信号通路调节TGF-β1诱导的EMT。正如Myr-PKI预处理细胞证实的那样，A2A受体的刺激减少了emt相关标记物的过表达，主要是通过camp依赖的PKA途径。A1和P2Y1受体刺激都加剧了TGF-β1驱动的效应，根据受体激活后ERK1/2磷酸化增加，MAPK抑制剂PD98059对细胞进行预处理可以降低TGF-β1驱动的效应。P2Y11受体激活诱导的效应被PKA或MAPK抑制相反调节，这与Gs-和gq偶联受体的双重性质一致。不同的是，在细胞长时间暴露于BzATP后，P2X7受体本身诱导的效应与TGF-β1相似，而不是相加性的。这些结果表明嘌呤受体可能是抗纤维化药物的靶点。
Epithelial to mesenchymal transition (EMT) occurs during embryogenesis or under pathological conditions such as hypoxia, injury, chronic inflammation, or tissue fibrosis. In renal tubular epithelial cells (MDCK), TGF-β1 induces EMT by reducing or increasing epithelial or mesenchymal marker expression, respectively. In this study, we confirmed that the cAMP analogues, 8-CPT-cAMP or N6-Ph-cAMP, inhibited the TGF-β1-driven overexpression of the mesenchymal markers ZEB-1, Slug, Fibronectin, and α-SMA. Furthermore, we showed that A1, A2A, P2Y1, P2Y11, and P2X7 purine receptor agonists modulated the TGF-β1-induced EMT through the involvement of PKA and/or MAPK/ERK signaling. The stimulation of A2A receptor reduced the overexpression of the EMT-related markers, mainly through the cAMP-dependent PKA pathway, as confirmed by cell pre-treatment with Myr-PKI. Both A1 and P2Y1 receptor stimulation exacerbated the TGF-β1-driven effects, which were reduced by cell pre-treatment with the MAPK inhibitor PD98059, according to the increased ERK1/2 phosphorylation upon receptor activation. The effects induced by P2Y11 receptor activation were oppositely modulated by PKA or MAPK inhibition, in line with the dual nature of the Gs- and Gq-coupled receptor. Differently, P2X7 receptor induced, per se, similar and not additive effects compared to TGF-β1, after prolonged cell exposure to BzATP. These results suggest a putative role of purine receptors as target for anti-fibrotic agents.
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影响因子：
56.9
作者：
Kawasaki, H;Springett, GM;Graybiel, AM
通讯作者：
Graybiel, AM
影响因子：
11.2
作者：
Ahmad A;Aboukameel A;Kong D;Wang Z;Sethi S;Chen W;Sarkar FH;Raz A
通讯作者：
Raz A
影响因子：
5
作者：
Impellizzeri, Daniela;Di Paola, Rosanna;Cuzzocrea, Salvatore
通讯作者：
Cuzzocrea, Salvatore
DOI：
10.1046/j.1440-1681.2001.03452.x
发表时间：
2001-04-01
影响因子：
2.9
作者：
Insel, PA;Ostrom, RS;Post, SR
通讯作者：
Post, SR
影响因子：
3.7
作者：
Azroyan A;Cortez-Retamozo V;Bouley R;Liberman R;Ruan YC;Kiselev E;Jacobson KA;Pittet MJ;Brown D;Breton S
通讯作者：
Breton S