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.

Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease / De Chiara, Letizia; Conte, Carolina; Semeraro, Roberto; Diaz-Bulnes, Paula; Angelotti, Maria Lucia; Mazzinghi, Benedetta; Molli, Alice; Antonelli, Giulia; Landini, Samuela; Melica, Maria Elena; Peired, Anna Julie; Maggi, Laura; Donati, Marta; La Regina, Gilda; Allinovi, Marco; Ravaglia, Fiammetta; Guasti, Daniele; Bani, Daniele; Cirillo, Luigi; Becherucci, Francesca; Guzzi, Francesco; Magi, Alberto; Annunziato, Francesco; Lasagni, Laura; Anders, Hans-Joachim; Lazzeri, Elena; Romagnani, Paola. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 13:(2022), pp. 0-0. [10.1038/s41467-022-33110-5]

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

De Chiara, Letizia;Conte, Carolina;Semeraro, Roberto;Diaz-Bulnes, Paula;Angelotti, Maria Lucia;Mazzinghi, Benedetta;Molli, Alice;Antonelli, Giulia;Landini, Samuela;Melica, Maria Elena;Peired, Anna Julie;Maggi, Laura;Donati, Marta;La Regina, Gilda;Allinovi, Marco;Ravaglia, Fiammetta;Guasti, Daniele;Bani, Daniele;Cirillo, Luigi;Becherucci, Francesca;Guzzi, Francesco;Magi, Alberto;Annunziato, Francesco;Lasagni, Laura;Anders, Hans-Joachim;Lazzeri, Elena
;
Romagnani, Paola
2022

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.
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De Chiara, Letizia; Conte, Carolina; Semeraro, Roberto; Diaz-Bulnes, Paula; Angelotti, Maria Lucia; Mazzinghi, Benedetta; Molli, Alice; Antonelli, Giulia; Landini, Samuela; Melica, Maria Elena; Peired, Anna Julie; Maggi, Laura; Donati, Marta; La Regina, Gilda; Allinovi, Marco; Ravaglia, Fiammetta; Guasti, Daniele; Bani, Daniele; Cirillo, Luigi; Becherucci, Francesca; Guzzi, Francesco; Magi, Alberto; Annunziato, Francesco; Lasagni, Laura; Anders, Hans-Joachim; Lazzeri, Elena; Romagnani, Paola
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1284474
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