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Kidney Week

Abstract: TH-OR011

Polyploidization Is Essential to Survive AKI but It Contributes to CKD Development

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • De Chiara, Letizia, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
  • Lazzeri, Elena, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
  • Angelotti, Maria Lucia, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
  • Conte, Carolina, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy
  • Romagnani, Paola, Excellence Center for Research, Transfer and High Education Denothe, University of Florence, Florence, Italy

Group or Team Name

  • Romagnani Lab
Background

Acute kidney injury (AKI) is a global health concern. If not lethal in the acute phase, AKI is considered reversible. However, even mild AKI episodes carry a risk of developing chronic kidney disease (CKD). Recently, we demonstrated that tubular epithelial cells (TECs) can undergo endoreplication-mediated hypertrophy after AKI. Endoreplications are incomplete cell cycles that lead to the formation of polyploid cells. As polyploid cells can provide increased cell function without restoring tissue integrity, we hypothesized that this mechanism is essential to survive AKI but it can be potentially maladaptive.

Methods

To address this hypothesis, we employed a series of in vitro and in vivo models based on the FUCCI technology to monitor cell cycle phasing in combination with YAP1 overexpression or downregulation. In the in vivo models, mice were subjected to unilateral ischemia reperfusion injury (IRI) to induce AKI. Polyploid cells have been then characterized by single cell RNAseq, cell sorting, super-resolution STED microscopy and transmission electron microscopy.

Results

In vitro, human renal tubular cells undergo polyploidization. The fraction of polyploid cells significantly decreases when YAP1 nuclear translocation is blocked. After AKI in mice, the inhibition of YAP1 significantly reduces the number of polyploid cells and worsens kidney function, while YAP1 overexpression leads to an increase in the number of polyploid cells up to 20% of all TECs. Electron microscopy and STED analysis revealed the presence of both mononucleated and binucleated polyploid cells with a chromatin distribution typical of actively transcribing cells. Strikingly, these mice appear to be more prone to develop tubulointerstitial fibrosis acquiring a marked senescent phenotype along with significant decline in renal function thus suggesting an association between polyploidization and CKD development. Indeed, isolation of polyploid cells proved that these cells actively transcribe and secrete pro-fibrotic and senescent factors thus confirming their role in CKD progression.

Conclusion

These data suggest that: 1) polyploidization is crucial to survive AKI by maintaining renal function in the acute phase and 2) polyploid cells are senescent and in the long run they are involved in the progression of AKI to CKD.