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Abstract: FR-PO183

Loss of Pax2 and Pax8 Induces Resistance to Ischemia in S3 Proximal Tubule

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • McElliott, Madison Chelise, University of Michigan, Ann Arbor, Michigan, United States
  • Telang, Asha Claire, University of Michigan, Ann Arbor, Michigan, United States
  • Otto, Edgar A., University of Michigan, Ann Arbor, Michigan, United States
  • Soofi, Abdul A., University of Michigan, Ann Arbor, Michigan, United States
  • Dressler, Greg R., University of Michigan, Ann Arbor, Michigan, United States
  • Beamish, Jeffrey A., University of Michigan, Ann Arbor, Michigan, United States

Pax2 and Pax8 are two highly homologous transcription factors regulating kidney development and are re-expressed during acute kidney injury (AKI) and repair. Our aim was to determine whether Pax2 and Pax8 are necessary to regenerate new proximal tubule cells after ischemic AKI.


Pax mutations were targeted to the proximal tubule, the primary site of injury in ischemic AKI, using floxed Pax2 and Pax8 conditional alleles and a phosphoenolpyruvate carboxykinase (PEPCK) Cre driver. Control mice included PEPCK-Cre but wild type Pax2 and Pax8 loci. All animals expressed a GFP-Cre reporter to track Cre activity. No gross differences in kidney function or histology were observed at baseline. Mutant and control mice were subjected to unilateral ischemia-reperfusion injury (uIRI) with simultaneous contralateral nephrectomy. Samples were analyzed at various post-injury time points. Nuclei from whole kidneys of uninjured mutant and control mice were analyzed using single nucleus RNA sequencing (snRNA seq).


Mice with proximal tubule Pax2 and Pax8 deletion were protected from both acute and chronic injury as measured by serum BUN, histological injury score, and expression of injury markers. Differences manifested as early as 6 h after injury, suggesting an inherent resistance to ischemia. Pre-injury snRNA seq revealed that mutant mice developed a unique population of S3 proximal tubule cells which was confirmed by immunostaining for cluster specific markers and invariably stained for GFP, marking Cre-mediated Pax2 and Pax8 deletion. The transcriptional profile of mutant S3 cells were strongly enriched in genes associated with a range of conditions that protect against ischemic injury including hypoxic preconditioning, caloric restriction, and female sex.


Our data indicate that neither Pax2 nor Pax8 is necessary for repair after ischemic AKI. On the contrary, Pax protein loss induced protection against ischemic injury by promoting a transcriptional program that strongly overlaps with other conditions that confer protection. These findings highlight critical genes and pathways that determine sensitivity to ischemic AKI and suggest a novel role for Pax proteins in the proximal tubule.


  • NIDDK Support