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Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation
Ruifeng Wang1,2, Titi Chen1, Chengshi Wang1
1Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
Insights
Inhibiting Fms-like tyrosine kinase 3 (Flt3) with AC220 reduced kidney injury and inflammation in a mouse model of focal segmental glomerulosclerosis (FSGS). This suggests Flt3 inhibitors may treat chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic kidney disease (CKD) is a global health issue with limited treatments.
- CD103+ dendritic cells (DCs) are implicated as pathogenic in adriamycin nephropathy (AN), a model for human focal segmental glomerulosclerosis (FSGS).
- Fms-like tyrosine kinase 3 (Flt3) is highly specific to tissue-resident CD103+ DCs.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting Flt3 signaling in CD103+ DCs for treating kidney injury.
- To evaluate the effect of a selective Flt3 inhibitor, AC220, on CD103+ DCs and kidney damage in a mouse model of AN.
Main Methods:
- Mice with adriamycin nephropathy (AN) were treated with a selective Flt3 inhibitor (AC220).
- Evaluated changes in CD103+ DCs, kidney function, injury markers, and inflammatory profiles.
- Assessed the impact on T cell populations and activation.
Main Results:
- AC220 treatment significantly decreased kidney CD103+ DCs in AN mice.
- AC220 administration improved kidney function, reduced injury and fibrosis, and lowered inflammatory cytokines (TNF-α, IL-1β, IL-6, CCL2, CCL5).
- Reduced infiltration and activation of CD4+ and CD8+ T cells were observed, linked to suppressed CD103+ DC-mediated T cell responses.
Conclusions:
- Flt3 inhibition via AC220 effectively mitigated kidney injury in the AN mouse model.
- AC220 demonstrates potential as a pharmaceutical agent for treating chronic kidney disease (CKD).
Background:
Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs.
Methods:
To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN.
Results:
Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103- DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice.
Conclusion:
Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.
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