Kidney Week

Abstract: FR-PO0683

Interferon Gamma Drives Rapidly Progressing Cystic Kidney Diseases

Session Information

• Cystic Kidney Diseases: Basic and Translational Research
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases

Authors

• Smith, Morgan E., The University of Oklahoma Health Sciences, Oklahoma City, Oklahoma, United States

Morgan E. Smith

• Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Katharina Hopp, PhD

• Zimmerman, Kurt, The University of Oklahoma Health Sciences, Oklahoma City, Oklahoma, United States

Kurt Zimmerman, PhD

Background

The rate of polycystic kidney disease (PKD) progression varies widely among patients and is influenced by multiple factors. Kidney injury is known to accelerate cystogenesis in mouse models of PKD, however the mechanisms underlying rapid disease progression remain unclear. Previous single cell RNA sequencing data from our lab identified the cytokine interferon gamma (IFNγ) as a potential driver of accelerated cyst growth following kidney injury. Based on these data, we hypothesized that IFNγ plays a critical role in promoting rapidly progressing PKD.

Methods

To test this, we crossed mice lacking IFNγ (Ifng^-/-) with our murine model of cystic kidney disease (Cagg Cre^ERT2 Ift88^f/f). At 8-10 weeks of age, mice were induced with tamoxifen followed by intraperitoneal injection of folic acid (FA) at 11-12 weeks of age to induce kidney injury; vehicle control mice received sodium bicarbonate solution. Kidneys were collected 56 days post-injury and disease severity was assessed by quantifying cystic index, fibrosis, and immune cell populations. To evaluate the role of IFNγ in a rapidly progressing, non-injured, model of PKD, we induced CaggCre^ERT2 Pkd2^f/f at postnatal day 7 (P7) via tamoxifen delivered through the nursing dam. Pups were treated 3 times per week for 3 weeks with anti-IFNγ antibody (XMG1.2) or isotype control (IgG1κ). Kidneys were collected at P28 for phenotypic analysis.

Results

Preliminary results indicate that genetic deletion of IFNγ significantly reduced injury-accelerated PKD severity, as evidenced by lower kidney weight to bodyweight ratio (2KW/BW) and cystic index. IFNγ deficiency also correlated with reduced kidney fibrosis and improved kidney function. Flow cytometry revealed fewer neutrophil and kidney resident macrophage (KRM) proportions. Similarly, antibody blockade of IFNγ in the non-injured Pkd2^f/f model led to a significant reduction in cyst burden and immune cell infiltration, mirroring the genetic knockout findings.

Conclusion

These findings suggest that IFNγ is a key mediator of rapid PKD progression, independent of injury. Targeting IFNγ signaling may represent a promising therapeutic strategy for slowing rapid PKD progression.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025366xmkpq