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Kidney Week

Abstract: TH-PO118

Polyploid Tubular Cells Promote Tubulointerstitial Fibrosis After AKI via TGF-β1 Activation

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: 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

We recently showed that tubular cell (TC) polyploidy is triggered by Acute Kidney Injury (AKI). Polyploid TC are required to promote survival in the early phase after AKI, but promote fibrosis and chronic kidney disease (CKD) progression in the long term. However, the molecular mechanism governing the link between polyploid TC and kidney fibrosis remains to be clarified.

Methods

We employed transgenic mouse models based on the FUCCI2aR reporter and in vivo single cell RNA-sequencing (scRNA-seq) to identify polyploid TC. In vitro scRNA-seq followed by sorting of polyploid TC was employed to characterize the expression profile of pro-fibrotic polyploid TC.

Results

Immediately after AKI, the expression of cell cycle markers identifies a population of DNA damaged polyploid TC. Polyploid TC accumulate DNA damage and survive, eventually resting in G1 phase of the cell cycle, while diploid TC die. In vivo and in vitro scRNA-seq along with sorting of polyploid TC show that these cells with DNA damage acquire a pro-fibrotic phenotype culminating in TGF-β1 expression. In vitro stimulation proved that TGF-β1 directly promotes TC polyploidization. In vivo interactome analysis revealed that TGF-β1 signaling fosters a reciprocal activation loop among polyploid TC, macrophages and fibroblasts to sustain kidney fibrosis and promote CKD progression.

Conclusion

Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI, supporting the existence of a tubulointerstitial crosstalk mediated by TGF-β1 signaling produced by polyploid TC with DNA damage. Finally, these results further demonstrate that TC polyploidization is a self-sustained mechanism.