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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease

Author

Listed:
  • Letizia Chiara

    (University of Florence)

  • Carolina Conte

    (University of Florence)

  • Roberto Semeraro

    (University of Florence)

  • Paula Diaz-Bulnes

    (Instituto de Investigación Sanitaria del Principado de Asturias ISPA)

  • Maria Lucia Angelotti

    (University of Florence)

  • Benedetta Mazzinghi

    (Meyer Children’s University Hospital)

  • Alice Molli

    (University of Florence
    Meyer Children’s University Hospital)

  • Giulia Antonelli

    (University of Florence)

  • Samuela Landini

    (Meyer Children’s University Hospital)

  • Maria Elena Melica

    (University of Florence)

  • Anna Julie Peired

    (University of Florence)

  • Laura Maggi

    (University of Florence)

  • Marta Donati

    (University of Florence)

  • Gilda Regina

    (University of Florence)

  • Marco Allinovi

    (Careggi University Hospital)

  • Fiammetta Ravaglia

    (Nephrology and Dialysis Unit, Santo Stefano Hospital)

  • Daniele Guasti

    (University of Florence)

  • Daniele Bani

    (University of Florence)

  • Luigi Cirillo

    (University of Florence
    Meyer Children’s University Hospital)

  • Francesca Becherucci

    (Meyer Children’s University Hospital)

  • Francesco Guzzi

    (Nephrology and Dialysis Unit, Santo Stefano Hospital)

  • Alberto Magi

    (University of Florence)

  • Francesco Annunziato

    (University of Florence
    Careggi University Hospital)

  • Laura Lasagni

    (University of Florence)

  • Hans-Joachim Anders

    (Department of Internal Medicine IV, LMU Hospital)

  • Elena Lazzeri

    (University of Florence)

  • Paola Romagnani

    (University of Florence
    Meyer Children’s University Hospital)

Abstract

Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors.

Suggested Citation

  • Letizia Chiara & Carolina Conte & Roberto Semeraro & Paula Diaz-Bulnes & Maria Lucia Angelotti & Benedetta Mazzinghi & Alice Molli & Giulia Antonelli & Samuela Landini & Maria Elena Melica & Anna Juli, 2022. "Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33110-5
    DOI: 10.1038/s41467-022-33110-5
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    References listed on IDEAS

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    1. Elena Lazzeri & Maria Lucia Angelotti & Anna Peired & Carolina Conte & Julian A. Marschner & Laura Maggi & Benedetta Mazzinghi & Duccio Lombardi & Maria Elena Melica & Sara Nardi & Elisa Ronconi & Ale, 2018. "Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
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