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Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation

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Abstract

In autosomal dominant polycystic kidney disease (ADPKD), renal cyst development and enlargement, as well as cell growth, are associated with alterations in several pathways, including cAMP and activator protein 1 (AP1) signalling. However, the precise mechanism by which these molecules stimulate cell proliferation is not yet fully understood. We now show by microarray analysis, luciferase assay, mutagenesis, and chromatin immunoprecipitation that CREB and AP1 contribute to increased expression of the amphiregulin gene, which codifies for an epidermal growth factor-like peptide, in ADPKD cystic cells, thereby promoting their cell growth. Increased amphiregulin (AR) expression was associated with abnormal cell proliferation in both PKD1-depleted and -mutated epithelial cells, as well as primary cystic cell lines isolated from ADPKD kidney tissues. Consistently, normal AR expression and proliferation were re-established in cystic cells by the expression of a mouse full-length PC1. Finally, we show that anti-AR antibodies and inhibitors of AP1 are able to reduce cell proliferation in cystic cells by reducing AR expression and EGFR activity. AR can therefore be considered as one of the key activators of the growth of human ADPKD cystic cells and thus a new potential therapeutic target.

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Acknowledgments

We thank Dr. Hirotaka Watanabe (Center for Neurologic Diseases, Louis Pasteur, Boston, USA) and Prof. James P. Calvet (Kidney Institute, University of Kansas, USA) for the CRE-Luc and 7×-AP1-Luc plasmids, respectively. We are grateful to Prof. Sean Lee and Prof. Kjetil Tasken (Biotechnology Center of Oslo, University of Oslo, Norway) for the AR-pGL2C and AR-pGL2C-ΔCRE plasmids, respectively. We also thank Dr. A. Canella (Dep. of Biochemistry and Molecular Biology, University of Ferrara) for cell cycle analysis, Dr. K. Dong for technical support on mouse Pkd1 knock-out cell lines, and Dr. V. Iannoni for carrying out some experiments. Finally, we thank Prof. P. Pinton for the access to imaging instruments and Dr. F. Vincenzi for 3H-thymidine incorporation analysis.

Work supported by grants from CaRiFe, CaRiCe, Italian MIUR COFIN 2008, and Regione Emilia Romagna (Ricerca Regione-Università) 2007–2009. The English was edited by Dr. Anna Forster.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Ferrara, via Fossato di Mortara, 74, 44121, Ferrara, Italy

    Gianluca Aguiari, Fabiana Bizzarri, Anna Bonon, Alessandra Mangolini & Laura del Senno

  2. Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy

    Eros Magri, Massimo Pedriali & Patrizia Querzoli

  3. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

    Stefan Somlo

  4. Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Peter C. Harris

  5. Division of Nephrology, S.Anna Hospital, Ferrara, Italy

    Luigi Catizone

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  1. Gianluca Aguiari
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  4. Alessandra Mangolini
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Correspondence to Gianluca Aguiari.

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Aguiari, G., Bizzarri, F., Bonon, A. et al. Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation. J Mol Med 90, 1267–1282 (2012). https://doi.org/10.1007/s00109-012-0902-3

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  • DOI: https://doi.org/10.1007/s00109-012-0902-3

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