A transcriptional network underlies susceptibility to kidney disease progression

Authors

  • Denise Laouari,

    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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    • These authors contributed equally to this work.

  • Martine Burtin,

    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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    • These authors contributed equally to this work.

  • Aurélie Phelep,

    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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  • Frank Bienaime,

    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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  • Laure-Hélène Noel,

    1. Service d'Anatomie Pathologique, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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  • David C. Lee,

    1. Office of the Vice President for Research, 609 Boyd Research Center, University of Georgia, Athens, GA, USA
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  • Christophe Legendre,

    1. Service de Transplantation Rénale Adulte, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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  • Gérard Friedlander,

    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
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  • Marco Pontoglio,

    1. INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Institut Cochin Département Génétique et Développement, Paris, France
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  • Fabiola Terzi

    Corresponding author
    1. INSERM U845, Centre de Recherche “Croissance et Signalisation”, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France
    • Tel: +33 144495245; Fax: +33 144490290

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Abstract

The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5′ UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression.

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