Abstract FR489: Drp1 in Myeloid Cells Protects Against Kidney Injury by Suppressing Dendritic Cell Activation and T Cell Accumulation
Lu, X; Liu, S; Kress, T; Chen, Y; Privratsky, J; Sesaki, H; Crowley, S
Published in: Hypertension
Dendritic cells (DCs) are implicated in the progression of chronic kidney disease (CKD), and emerging evidence demonstrates that metabolic reprogramming profoundly influences DC differentiation and activation. Dynamin-related protein 1 (Drp1), a central regulator of mitochondrial fission, modulates mitochondrial metabolism; however, its role in DC-mediated immune responses remains unclear. To investigate the role of myeloid Drp1 in regulating DC function and CKD, we generate CD11c-specific Drp1 knockout mice (Drp1 MKO) by breeding
with
mice. Drp1 expression was significantly reduced in splenic DCs (0.45 ± 0.01 vs. 1.0 ± 0.09 au;
<0.001) and BMDCs (0.20 ± 0.003 vs. 1.0 ± 0.009 au;
<0.001) from Drp1 MKO compared to wild-type (WT) mice. At baseline, Drp1 MKO mice had normal kidneys and similar renal immune cell profiles compared WT mice. However, following nephrotoxic serum (NTS)-induced CKD, Drp1 MKO mice showed higher mortality (50% vs. 10%;
=0.057), elevated BUN levels (178 ± 23 vs. 91 ± 14 mg/dL; p<0.05), and more severe kidney injury and inflammation, as corroborated by increased mRNA expression of kidney injury and inflammation markers, including
(3.0 ± 0.54 vs. 1.0 ± 0.26 au;
=0.015),
(5.3 ± 1.4 vs. 1.0 ± 0.3 au;
=0.024),
(1.6 ± 0.17 vs. 1.0 ± 0.19 au;
=0.068),
(3.5 ± 0.71 vs. 1.0 ± 0.23 au;
=0.015), and
(2.3 ± 0.44 vs. 1.0 ± 0.40 au;
=0.077). Costimulatory molecules on DCs provide the second signal required for effective T cell priming and promote clonal expansion of T cells. During NTS-induced CKD, Drp1 MKO kidneys exhibited increased numbers of CD86
DCs (1.92 ± 0.17 vs. 1.15 ± 0.25 X10
/g; p=0.035) and T cells (20.2 ± 1.2 vs. 13.0 ± 1.7 X10
/g; p=0.01) compared to WT mice. Furthermore, Drp1 MKO kidneys had elevated numbers of effector memory T cells (CD44
CD62
, 10.01 ± 0.60 vs. 7.23 ± 0.98 X10
/g; p=0.047) and tissue-resident memory T cells (CD69
, 6.63 ± 0.38 vs. 4.21 ± 0.39 X10
/g; p=0.002) compared to WT controls. These findings suggest that Drp1 in DCs protects against NTS-induced CKD by limiting DC-mediated T cell activation.
