Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells

Valentina Di Liberto, Giuseppa Mudo', Natale Belluardo, Mariachiara Zuccarini, Margherita Rossini, Marzia Carluccio, Daniele Filippo Condorelli, Francesco Caciagli, Patrizia Di Iorio, Renata Ciccarelli, Michel Piers Rathbone, Silvana Buccella, Patricia Giuliani

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Abstract

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.
Lingua originaleEnglish
pagine (da-a)429-442
Numero di pagine14
RivistaPurinergic Signalling
Volume13
Stato di pubblicazionePublished - 2017

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cita questo

Di Liberto, V., Mudo', G., Belluardo, N., Zuccarini, M., Rossini, M., Carluccio, M., Condorelli, D. F., Caciagli, F., Di Iorio, P., Ciccarelli, R., Rathbone, M. P., Buccella, S., & Giuliani, P. (2017). Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells. Purinergic Signalling, 13, 429-442.