Kidney Week

Abstract: SA-PO459

Genetic Strain Influences Infiltrating Macrophage Subtype, Accumulation, and Gene Expression in the Liver of a Mouse Model of Hepatorenal Fibrocystic Disease

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

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

Kurt Zimmerman,

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

Zhang Li,

• 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

Hepatorenal fibrocystic disease (HRFCD) is a genetically inherited disorder in which patients display significant heterogeneity in disease severity and progression with varying levels of fibrosis, cyst development, and inflammation. Recent data indicate that macrophage subtypes promote renal cystic disease suggesting that the subtype of macrophage present controls phenotypic outcome.

Methods

Herein, we utilize a mouse model of HRFCD (Ift88^Orpk mice) on the C57BL/6 and BALB/C inbred backgrounds to study the influence of genetic strain on macrophage accumulation and disease progression in the liver.

Results

Phenotypic analysis of liver tissue shows that C57BL/6 Ift88^Orpk livers have increased cystic severity but reduced levels of fibrosis compared to BALB/c Ift88^Orpk livers. Further, our data show that genetic strain influences the subtype of infiltrating macrophage present during normal postnatal liver development and in Ift88^Orpk mice (Ly6c^lo in C57BL/6 vs Ly6c^hi in BALB/c). RNA sequencing data indicate that macrophages and cholangiocytes express unique ligand receptor pairs, dependent on genetic strain, that may facilitate epithelial cyst expansion or fibrosis. To test the importance of Ly6c^hi infiltrating macrophages in promoting the fibrosis observed in BALB/c Ift88^Orpk mice, we crossed these mice onto a CCR2-/- background. Our data indicate that CCR2 deficiency reduces Ly6c^hi macrophage accumulation and prevents the increase in Col1a1 and Col3a1 gene expression in Ift88^Orpk mice.

Conclusion

Collectively, our data suggest that the heterogeneity in the hepatic phenotype associated with ciliopathies is influenced by the subtype of infiltrating macrophage that is present.

Funding

• NIDDK Support