Kidney Week

Abstract: FR-PO579

Lyve1+ Macrophages Play No Role in Initiating Polycystic Kidney Disease

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Wilson, Laura, University College London, London, United Kingdom

Laura Wilson,

• Woolf, Adrian S., The University of Manchester, Manchester, United Kingdom

Adrian S. Woolf,

• Long, David A., University College London, London, United Kingdom

David A. Long,

Background

Recent studies show macrophages modulate progression of polycystic kidney disease (PKD). As examples, depletion of macrophages chemically with clodronate or genetically by deleting macrophage chemoattractant protein 1 (MCP1) reduces PKD severity. We hypothesised that a specific population of macrophages may be needed to initiate kidney cystogenesis.

Methods

We characterised macrophage subpopulations in cystic Cpk and Pkd1^RC mouse kidneys from the embryonic period. Additionally, we specifically depleted Lyve1⁺ macrophages by crossing Lyve1-Cre with Csf1r-floxed mice in the context of wild type and Cpk mice.

Results

Using macrophage-specific markers F4/80 and CD11b, we identified two populations of macrophages (F4/80^hiCD11b^lo and F4/80^loCD11b^hi) by flow cytometry. CD206, Lyve1, TIMD4 and CCR2 markers were used to further characterise the subpopulations. Renal F4/80^hiCD11b^lo macrophages were CD206⁺, some expressed Lyve1 and some were TIMD4⁺. F4/80^loCD11b^hi macrophages were CCR2⁺ and negative for the other markers. At embryonic day 18.5, when homozygous Cpk and Pkd1^RC mutant mice have dilated tubules, there was a significant increase in the proportion of Lyve1⁺ macrophages in mutant compared with wild-type kidneys, with no changes in other populations. By studying a detailed time course of Cpk disease progression, we observed the initial accumulation of Lyve1⁺ macrophages was followed by an increase in F4/80^hiCD11b^lo macrophages in kidneys as cysts initiate. All macrophage populations were significantly increased in severely cystic kidneys. Depleting Lyve1⁺ macrophages did not compromise kidney development in non-PKD-mutant mice, with no significant change in glomerular numbers in Lyve1-Cre Csf1r^fl/fl embryos. There were no differences in PKD severity between Cpk^-/- and Lyve1⁺ macrophage-depleted Cpk^-/- mice based on kidney/body weight, renal cystic index and blood urea nitrogen two weeks after birth.

Conclusion

Lyve1⁺ macrophages accumulate before PKD cysts initiate during embryonic development. Genetic depletion of Lyve1⁺ macrophages from this period, however, does not affect the severity of PKD.