Kidney Week

Abstract: FR-PO621

Exploring the Role of Interferon-Gamma in Injury-Accelerated Cystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | 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: Cystic

Authors

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

Kurt Zimmerman, PhD

Background

Acute kidney injury (AKI) accelerates cystogenesis in mouse models of polycystic kidney disease (PKD); however, the mechanism underlying this acceleration remains unclear. Previous data from our lab indicate that genetic deletion of adaptive immune cells (T and B cells) rescues injury accelerated PKD. Additionally, single cell RNA sequencing data suggest that the cytokine interferon gamma (IFNγ), which is produced by CD4+ and CD8+ T cells, is responsible for driving the injury accelerated phenotype. Based on these data, we hypothesize that IFNγ is a significant contributor to injury accelerated PKD.

Methods

To test if IFNγ is essential for injury accelerated cystic disease, 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. Sodium bicarbonate solution was used as a vehicle control. Kidneys were collected 56 days post-injury and the PKD phenotype was measured by quantifying cystic index and cyst number.

Results

Analysis of preliminary data indicate that loss of IFNγ significantly reduced the severity of PKD as measured by 2KW/BW, cystic index, cystic number, and cyst size compared to controls. Likewise, loss of IFNγ was associated with reduced kidney fibrosis and improved kidney function. Analysis of immune cell numbers via flow cytometry indicate that loss of IFNγ significantly reduced the number of neutrophils and kidney resident macrophages (KRM) compared to controls. To test if CD4+ or CD8+ T cell-derived IFNγ was responsible for the observed phenotypic rescue in IFNγ deficient mice, we crossed mice deficient in CD4+ or CD8+ T cells to our mouse model of cystic kidney disease. Analysis of preliminary data indicate that loss of CD4+ T cells, but not CD8+ T cells, was associated with improved phenotypic outcome following FA induced injury. Loss of CD4+ T cells, but not CD8+ T cells, also reduced the number of KRM and neutrophils following FA induced injury.

Conclusion

Collectively, our data suggest that CD4+ T cell-derived IFNγ drives injury accelerated cystic kidney disease.

Funding

• NIDDK Support