Modulation of the TGF-β1-induced epithelial to mesenchymal transition EMT mediated by P1 and P2 purine receptors in MDCK cellsReportar como inadecuado

Modulation of the TGF-β1-induced epithelial to mesenchymal transition EMT mediated by P1 and P2 purine receptors in MDCK cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Purinergic Signalling

pp 1–14

First Online: 14 June 2017Received: 12 January 2017Accepted: 29 May 2017DOI: 10.1007-s11302-017-9571-6

Cite this article as: Zuccarini, M., Giuliani, P., Buccella, S. et al. Purinergic Signalling 2017. doi:10.1007-s11302-017-9571-6


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.

KeywordsP1-P2 purinergic receptors Epithelial to mesenchymal transition Fibrosis Transforming growth factor β1 Madin Darby canine kidney cells Mariachiara Zuccarini and Patricia Giuliani are co-first authors.

Autor: Mariachiara Zuccarini - Patricia Giuliani - Silvana Buccella - Valentina Di Liberto - Giuseppa Mudò - Natale Belluardo - Ma


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