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Kidney Week

Abstract: FR-PO603

Studying the Involvement of the Complement Receptor C5ar1 in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Cordova, Audrey M., The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Pan, Aaron, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Maryam, Bibi, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Hopp, Katharina, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Zimmerman, Kurt, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Background

Polycystic Kidney Disease (PKD) is caused by mutations in cilia-related genes and results in fluid-filled cysts throughout the kidney. Previous data indicates that immune cells, in particular macrophages, are important in regulating the progression of cystic disease. To understand possible functions of macrophages in cystic kidney disease, our lab performed single cell RNA sequencing (scRNAseq) on macrophages isolated from control and cystic mice. scRNAseq data indicate that kidney resident macrophages isolated from cystic mice have increased expression of the complement 5a receptor 1 (C5ar1) gene. C5ar1 is a G-protein coupled receptor that binds to the anaphylatoxin C5a that promotes inflammation and macrophage recruitment.

Methods

To test the importance of C5ar1 in cyst progression, we crossed C5ar1 deficient mice onto two different cystic backgrounds (Pkd1RC/RC and Cagg CreERT2 Ift88fl/fl) and analyzed PKD severity and immune cell numbers using flow cytometry.

Results

Preliminary analysis of Pkd1RC/RC C5ar1-/- mice at three months of age indicate no effect on PKD phenotype compared to controls. In contrast, loss of C5ar1 significantly worsened the PKD phenotype in Pkd1RC/RC mice compared to controls at 1 year of age. Likewise, loss of C5ar1 in adult induced Ift88 mice resulted in worsened PKD phenotype when analyzed 6-7 months post induction (~9 months of age). Analysis of flow cytometry data in 1 year old Pkd1RC/RC and 9 month old Ift88 mice revealed that loss of C5ar1 resulted in significantly more Ly6clo monocytes, CD4+ T cells, and CD8+ T cells compared to controls. Surprisingly, loss of C5ar1 resulted in significantly fewer Mrc1+/Trem2+ KRM in Pkd1RC/RC mice but significantly more Mrc1+/Trem2+ KRM in Ift88 mice.

Conclusion

Collectively, our data suggest that C5ar1 restricts PKD progression, possibly through modulation of adaptive immune cell accumulation.

Funding

  • NIDDK Support