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

Letizia Chiara, Carolina Conte, Roberto Semeraro, Paula Diaz-Bulnes, Maria Lucia Angelotti, Benedetta Mazzinghi, Alice Molli, Giulia Antonelli, Samuela Landini, Maria Elena Melica, Anna Julie Peired, Laura Maggi, Marta Donati, Gilda Regina, Marco Allinovi, Fiammetta Ravaglia, Daniele Guasti, Daniele Bani, Luigi Cirillo, Francesca Becherucci, Francesco Guzzi, Alberto Magi, Francesco Annunziato, Laura Lasagni, Hans-Joachim Anders, Elena Lazzeri () and Paola Romagnani ()
Additional contact information
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
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
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33110-5

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DOI: 10.1038/s41467-022-33110-5

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