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Kidney Week

Abstract: FR-PO958

Kidney Tubule Polyploidization Is a Novel Target to Block CKD Progression After AKI

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
  • Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
  • Romagnani, Paola, Universita degli Studi di Firenze, Firenze, Toscana, Italy
Background

Acute Kidney Injury (AKI) is characterized by a rapid deterioration of kidney function and represents a global healthcare issue. In addition, AKI survivors frequently develop chronic kidney disease (CKD). Tubular epithelial cells (TC) respond to AKI by triggering polyploidy, a condition in which a normally diploid cell acquires additional sets of chromosomes. Polyploidy offers several advantages and in the kidney we have demonstrated to be an adaptive response to survive after AKI. However, polyploidization in the absence of damage drives CKD progression. Building on these novel paradigms we hypothesized that: 1) polyploid TC are a heterogeneous population with distinctive features and 2) polyploid TC may represent a novel target to successfully prevent CKD progression.

Methods

We employed in vivo models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology in combination with YAP1 modulation or conditional deletion. In these models, mice were subjected to ischemia reperfusion injury or nephrotoxic AKI. Mice were treated with different combination of compounds at different times and analyzed by single cell-RNA sequencing (scRNA-seq) analysis, cell sorting, FACS analysis, super-resolution microscopy.

Results

After AKI, YAP1 is activated triggering TC polyploidization. Conditional TC deletion of YAP1 resulted in a reduced number of polyploid cells, worsened kidney function and a dramatic reduction of mouse survival. However, delayed block of YAP1-driven polyploidy after AKI by pharmacological inhibition prevented AKI-CKD transition by attenuating continuous cycles of polyploidization in TC. Senolytic therapy proved that cycling polyploid TC were responsible for the senescent profibrotic phenotype acquired over the time by polyploid TC and the primary trigger of CKD progression. scRNA-seq and tubular specific YAP1 deletion triggered after AKI excluded any systemic effect of compound administration and demonstrated that the observed protective effect is mediated exclusively by TC and not by other cells.

Conclusion

In conclusion, we demonstrated that: 1) continuously cycling polyploid TC and not growth arrested polyploid TC are senescent and the primary driver of CKD; 2) blocking cycling polyploid TC in the right window of opportunity is sufficient to prevent AKI-CKD transition with important translational implications in clinical setting.