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Kidney Week

Abstract: SA-PO088

Contralateral Nephrectomy After AKI Leads to Functional Recovery by Stimulating Epithelial Progenitor Proliferation Whilst Inhibiting Endocycling-Related Hypertrophy

Session Information

  • AKI: Mechanisms - III
    November 05, 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

  • Moonen, Lies, Universiteit Antwerpen, Antwerpen, Antwerp, Belgium
  • Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
  • Peired, Anna Julie, Universita degli Studi di Firenze, Firenze, Toscana, Italy
  • Conte, Carolina, 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, Toscana, Italy
  • Vervaet, Benjamin Arthur, Universiteit Antwerpen, Antwerpen, Antwerp, Belgium
Background

Clinical studies of the last decade identified acute kidney injury (AKI) as an important risk factor for the development of chronic kidney disease (CKD). Hence, strategies to improve the reparative efficiency are of great therapeutic interest. We established a murine model in which the functional and histological recovery of a kidney is drastically enhanced by removal of the unharmed contralateral kidney, i.e. nephrectomy-induced recovery. It is unknown whether nephrectomy (Nx) achieves this by stimulating true epithelial regeneration and/or hypertrophy. Insight in the mechanisms underlying efficient nephrectomy-induced recovery may open new therapeutic strategies.

Methods

AKI was induced in 2 specific transgenic mouse lines by left unilateral ischemia/reperfusion (UIRI) for 21 min at 34°C, after which either right Nx or no Nx was performed 3 days later. Mice were euthanized 7 and 28 days after UIRI for functional and renal histopathological analyses. Pax2/Confetti mice were applied to track proliferation of individual genetically labeled tubular progenitor cells by histological clone size frequency analysis. Pax8/FUCCI2aR mice were included to assess TEC hypertrophy (i.e. endocycling) by combining DNA content analysis via flow cytometry with expression analysis of genetic fluorescent cellular labels that reveal the cell cycle stage.

Results

Nx performed at day 3 after UIRI was confirmed to rescue function and histology. Clonal analysis in PAX2/Confetti mice revealed that Nx significantly stimulated individual progenitor cell proliferation as compared to no Nx and Nx recruited more progenitor cells to start proliferation as compared to no Nx. Analyses of FUCCI mice revealed that Nx prevented accumulation of hypertrophic (endocycling) TECs (i.e. polyploid cells with ≥8C DNA content).

Conclusion

Nx-enhanced regeneration is driven by a stimulated clonal expansion of renal progenitor cells that significantly surpasses that of spontaneous repair after UIRI. Moreover, Nx attenuates the build-up of polyploid/hypertrophic epithelial cells. Hence, Nx stimulates recovery by promoting true epithelial regeneration, whilst suppressing endocylce-mediated hypertrophy.