FLT3 INHIBITOR ATTENUATES RENAL INJURY IN ADRIAMYCIN NEPHROPATHY BY SUPPRESSING CD103+ DC-MEDIATED T CELL ACTIVATION

Q CAO1, R WANG1, T CHEN1, P RAO1, Z ZHANG1, VENCENT LEE1, G ZHENG1, Y WANG1, DC HARRIS1

 1The Westmead Institute for Medical Research, The University of Sydney, NSW.

Aim and Background:

Chronic kidney disease (CKD) is a global public health problem, and lacks effective treatments. In our previous study, CD103+ DCs were shown to play a pathogenic role in Adriamycin nephropathy (AN), a model of focal sclerosing GN. FMS-like tyrosine kinase 3 (Flt3) is a receptor which is highly and specifically expressed on tissue resident CD103+ DCs. To test the effect on renal injury of inhibition of Flt3 on CD103+ DCs, we used a selective Flt3 inhibitor (AC220) to treat mice with AN.

Methods:

AN was induced in BALB/c mice, who were treated daily for 14 days with 10mg/kg AC220 or Vehicle (n=8/group) from day 7 after adriamycin, when AN was established. Renal functional and structural injury, as well as inflammatory cytokine expression and cell infiltration were assessed.

Results:

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 renal function and reduced the renal injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines of IL-1beta, IL-6 and TNF-a. AC220 treatment decreased infiltration of CD4 T cells, CD8 T cells and macrophages in kidney, and reduced inflammatory cytokine and cytotoxic molecule expression of kidney CD8 T cells in AN mice.

Conclusions:

Flt3 inhibitor AC220 effectively reduced renal injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat chronic kidney disease.

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The ASM is hosted by Australian and New Zealand Society of Nephrology.

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