Kidney Week

Abstract: SA-PO460

CD206+ Resident Macrophages Are Associated with Cyst Progression in Juvenile-Induced Cilia Mutant Mouse Models

Session Information

• Cystic Kidney Diseases: Basic/Translational
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Li, Zhang, University of Alabama at Birmingham, Birmingham, Alabama, United States

Zhang Li,

• Zimmerman, Kurt, University of Alabama at Birmingham, Birmingham, Alabama, United States

Kurt Zimmerman,

• George, James F., University of Alabama at Birmingham, Birmingham, Alabama, United States

James F. George,

• Mrug, Michal, University of Alabama at Birmingham, Birmingham, Alabama, United States

Michal Mrug,

• Yoder, Bradley K., University of Alabama at Birmingham, Birmingham, Alabama, United States

Bradley K. Yoder,

Background

Abnormalities in the function (Pkd1 or Pkd2 mutation) or structure (Ift88 mutation) of primary cilia result in renal cysts in animal models and human patients. Recent studies show that removing cilia in mouse models of Pkd1or Pkd2 inactivation suppresses cyst growth suggesting a primary cilia-dependent suppressor function in cystogenesis. It has been reported that renal resident macrophages are associated with cyst formation; however, the importance of resident macrophage subsets in promoting renal cyst formation and their relationship with cystic disease caused by mutations in proteins required for cilia formation (Ift88) or function (Pkd2) is unknown.

Methods

To test the association of resident macrophage subtypes with the type of cilia mutation, we performed flow cytometry analysis of kidneys harvested from juvenile induced conditional Ift88, Pkd2,or Ift88:Pkd2 mutant mice. We also used pharmacological (CSF1R kinase inhibitor) and genetic (CX3CR1^gfp/gfp) approaches to test the functional importance of resident macrophages in juvenile-induced cyst formation.

Results

Our data indicate that induction of cilia dysfunction (Pkd2 mutation) in juvenile mice results in more severe cysts 21 days post induction compared to mice lacking primary cilia alone (Ift88 mutation) or mice lacking both Pkd2 and Ift88. Analysis of flow cytometry data indicate that the number of CD206+ resident macrophages is directly correlated with the severity of cystic disease with juvenile-induced Pkd2 deficient mice having the greatest number of CD206+ resident macrophages. Further, we show that Ift88:Pkd2 double mutant mice have an intermediate cystic severity and number of CD206+ resident macrophages compared to single Ift88 andPkd2 mutant mice. Finally, our preliminary data indicate that inhibition of CD206+ resident macrophage accumulation using a CSF1R kinase inhibitor or genetic reduction of CD206+ resident macrophages using a CX3CR1^gfp/gfp mouse reduced the severity of cystic disease in juvenile-induced Ift88 mutant mice.

Conclusion

These data suggest that the type of primary cilia mutation controls the abundance of CD206+ resident macrophages and these resident macrophages are important in promoting cyst progression.