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Kidney Week

Abstract: TH-PO141

Tubular Cell Polyploidization Leads to a Senescent Profibrotic Phenotype and Is a Trigger of CKD

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

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

The occurrence of polyploidization in tubular epithelial cells (TC) is a process that increases the DNA content in TC in response to acute kidney injury (AKI). Evolutionary, polyploidy appears to be developed to tolerate conditions of high metabolic demand, sustaining a temporary functional recovery that is not accompanied by structural recovery leading over time to tissue fibrosis. The association of tissue polyploidization, senescence, and fibrosis has been demonstrated in other organs but in the kidney is currently unknown. In this study, we aimed to 1) characterize TC undergoing polyploidy, 2) investigate whether post-AKI fibrosis and senescence could be a consequence of TC polyploidization and 3) whether the latter is a driver of chronic kidney disease (CKD) development.

Methods

We performed single cell RNA-sequencing (scRNA-seq) on mouse kidneys after unilateral ischemia reperfusion injury to identify polyploid TC signature. In addition, we employed a conditional transgenic mouse model of increased polyploidization (Pax8/SAV1ko mice) and a treatment with senolytics was used followed by FACS and confocal microscopy analysis.

Results

scRNA-seq analysis revealed clusters of proximal TC enriched in genes associated with endoreplication-mediated polyploidy. A trajectory analysis suggested that TC polyploidization started with increased ribosome biogenesis, followed by YAP1 activation and culminated with a pro-fibrotic and senescent signature, suggesting polyploid TC may acquire a senescent phenotype. Indeed, polyploid TC progressively accumulate in the kidney as the mice aged and correlated with GFR decline and senescence. Importantly, sustained TC polyploidization in Pax8/SAV1ko mice was accompanied by increased senescence, fibrosis and a progressive kidney function decline, i.e. CKD. Isolation of polyploid TC proved that they actively transcribe and secrete pro-fibrotic and senescent factors. However, senolytic treatment demonstrated that removal of senescent polyploid TC in Pax8/SAV1ko mice was sufficient to halt CKD progression.

Conclusion

We have shown that:1) polyploid TC exhibits a pro-fibrotic and senescent signature;2) TC polyploidization leads to senescence, fibrosis and progression of CKD;3) senolytics can block further ongoing polyploidization of TC, abolishing their senescent profibrotic phenotype and preventing CKD.