Kidney Week

Abstract: FR-OR02

Kidney Tubule Polyploidization Is an Evolutionary Conserved Mechanism Required to Survive AKI

Session Information

• AKI: Novel Mechanisms and Targets of Injury
  November 05, 2021 | Location: Simulive, Virtual Only
  Abstract Time: 04:30 PM - 06:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Letizia De Chiara, PhD

• Conte, Carolina, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Carolina Conte,

• Angelotti, Maria Lucia, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Maria Lucia Angelotti,

• Antonelli, Giulia, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Giulia Antonelli,

• Peired, Anna Julie, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Anna Julie Peired,

• Melica, Maria elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Maria elena Melica,

• Mazzinghi, Benedetta, Azienda Ospedaliero Universitaria Meyer, Firenze, Toscana, Italy

Benedetta Mazzinghi,

• Lasagni, Laura, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Laura Lasagni,

• Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Elena Lazzeri,

• Romagnani, Paola, Universita degli Studi di Firenze, Firenze, Toscana, Italy

Paola Romagnani,

Background

Acute Kidney Injury (AKI) is characterized by a rapid deterioration of kidney function. Recently, we showed that tubular epithelial cells (TEC) respond to AKI by triggering polyploidy, a condition in which a normally diploid cell acquires additional sets of chromosomes. Polyploidy offers several advantages, but in the kidney the biological significance of polyploidization remains unclear. In this study we hypothesized that polyploidy 1) is the predominant cellular response during AKI and 2) is an adaptive stress response required to maintain a residual kidney function to assure survival.

Methods

To address these hypotheses, we employed in vivo transgenic models based on the Confetti reporter and the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology in combination with YAP1 downregulation. Mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by single cell-RNA sequencing analysis, cell sorting, FACS analysis, super-resolution and transmission electron microscopy.

Results

After AKI, YAP1 is activated driving TEC polyploidization. Polyploid TEC increase in parallel to massive cell death triggered by AKI suggesting that polyploidization could be a means to escape cell death. Indeed, we found that polyploid TEC tend to accumulate genome instability and survive, while diploid TEC do not. Of note, virtually all dying cells were cycling cells based on the FUCCI reporter suggesting that TEC death occurred during the S or G2/M phase. As polyploid TEC increase immediately following AKI, they may be required to survive injury and damage by sustaining renal function. In order to evaluate the functional role of polyploid cells during AKI, we generated YAP1ko mice, where YAP1 is knocked-out specifically in TEC. Indeed, after AKI, YAP1ko mice showed a reduced number of polyploid cells, worsened kidney function and a dramatic reduction of mouse survival, proving that polyploidization is required to survive AKI.

Conclusion

In conclusion, we demonstrated that after AKI: 1) TEC accumulate genome instability and die or become polyploidy; 2) TEC polyploidy is essential to preserve residual kidney function allowing survival.