In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 10 ( 2019-10), p. 1841-1856
Abstract:
Disruption of cilia function before postnatal day 12–14 in mice or renal injury in adult mice with cilia dysfunction results in accelerated renal cyst formation. Macrophages have been implicated in promoting cyst formation; however, it is unclear whether infiltrating bone marrow-derived or kidney resident macrophages are responsible. The authors show that a specific population of juvenile-like resident macrophages are present during periods of accelerated cyst formation. Inhibition of juvenile-like resident macrophage accumulation using a colony-stimulating factor 1 receptor kinase inhibitor reduced the severity of cystic disease in two different animal models of cystic disease. These results suggest resident renal macrophages contribute to cystic disease. Background Mutations affecting cilia proteins have an established role in renal cyst formation. In mice, the rate of cystogenesis is influenced by the age at which cilia dysfunction occurs and whether the kidney has been injured. Disruption of cilia function before postnatal day 12–14 results in rapid cyst formation; however, cyst formation is slower when cilia dysfunction is induced after postnatal day 14. Rapid cyst formation can also be induced in conditional adult cilia mutant mice by introducing renal injury. Previous studies indicate that macrophages are involved in cyst formation, however the specific role and type of macrophages responsible has not been clarified. Methods We analyzed resident macrophage number and subtypes during postnatal renal maturation and after renal injury in control and conditional Ift88 cilia mutant mice. We also used a pharmacological inhibitor of resident macrophage proliferation and accumulation to determine the importance of these cells during rapid cyst formation. Results Our data show that renal resident macrophages undergo a phenotypic switch from R2b (CD11c lo ) to R2a (CD11c hi ) during postnatal renal maturation. The timing of this switch correlates with the period in which cyst formation transitions from rapid to slow following induction of cilia dysfunction. Renal injury induces the reaccumulation of juvenile-like R2b resident macrophages in cilia mutant mice and restores rapid cystogenesis. Loss of primary cilia in injured conditional Ift88 mice results in enhanced epithelial production of membrane-bound CSF1, a cytokine that promotes resident macrophage proliferation. Inhibiting CSF1/CSF1-receptor signaling with a CSF1R kinase inhibitor reduces resident macrophage proliferation, R2b resident macrophage accumulation, and renal cyst formation in two mouse models of cystic disease. Conclusions These data uncover an important pathogenic role for resident macrophages during rapid cyst progression.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2018080810
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
2029124-3
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