Abstract: SA-OR58
Kidney Tubule Polyploidization Drives CKD Progression After AKI
Session Information
- CKD: Cutting Edge of Mechanisms
November 06, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Conte, Carolina, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Angelotti, Maria Lucia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Antonelli, Giulia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Peired, Anna Julie, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Melica, Maria elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Mazzinghi, Benedetta, Azienda Ospedaliero Universitaria Meyer, Firenze, Toscana, Italy
- Lasagni, Laura, 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. In addition, AKI survivors frequently develop chronic kidney disease (CKD). The traditional concept of kidney function recovery after AKI is based on a widespread proliferative capacity of injured tubular epithelial cells (TEC), which however is incompatible with the high prevalence of CKD after AKI. We recently demonstrated that TEC respond to AKI not only by proliferation, but also by undergoing polyplodization i.e. acquire more than one pair of chromosomes. Physiologically, polyploidy offers several advantages such as rapid adaptation to stress, compensation for cell loss and enhanced cell function. However, as polyploid cells can provide functional restoration but not structural recovery they can potentially drive CKD progression
Methods
We employed in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology in combination with YAP1 overexpression or inhibition. In these models, mice were subjected to 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 triggering TEC polyploidization. In YAP1 overexpressing mice, a sustained activation of TEC polyploidization after AKI reduces early acute function loss but aggravates fibrosis, senescence caused by AKI, and AKI to CKD transition. Indeed, healthy YAP1 overexpressing mice present a consistent decline of kidney function over time suggesting an association between increased polyploidy and CKD development. Isolation of polyploid cells proved that these cells transcribe pro-fibrotic and senescent factors thus confirming their role in CKD progression. Importantly, as polyploid TEC become detrimental over time, blocking YAP1-driven polyploidy in a time-dependent manner avoids CKD development in comparison to control mice.
Conclusion
Collectively, these data suggest that: 1) polyploid TEC are pro-fibrotic leading in the long run to CKD progression; 2) blocking polyploidization in the right window of opportunity, can successfully ameliorate CKD progression after AKI.