ORF06-04 - SLAMF3-Driven T Cell Activation Induces Podocyte Injury via IL-17RA-PI3K-NF-Κb Signaling in Diabetic Kidney Disease

Objective

Insulin resistance plays a central role in the pathogenesis of diabetic kidney disease (DKD), yet the immunometabolic mechanisms linking insulin resistance to podocyte injury remain incompletely understood. We previously identified signaling lymphocyte activation molecule family 3 (SLAMF3) as an insulin resistance-responsive molecule on T cells. Here, we investigated whether SLAMF3-mediated T cell activation contributes to podocyte injury in DKD.

Methods

Human CD4? T cells were stimulated with palmitic acid (PA) to model lipid-induced insulin resistance, followed by assessment of SLAMF3 and IL-17 expression. A transwell co-culture system was used to examine the effects of PA-treated T cells on human podocytes. Podocyte injury and signaling pathways were evaluated using RNA sequencing, immunoblotting, and transmission electron microscopy. Mechanistic studies included IL-17A/F neutralization and CRISPR-Cas9-mediated SLAMF3 deletion in CD4? T cells. In vivo validation was performed in C57BL/6J mice fed a high-fat diet (HFD).

Results

PA stimulation induced a dose-dependent increase in SLAMF3 expression and IL-17 secretion in CD4? T cells. Podocytes co-cultured with PA-treated T cells exhibited reduced nephrin and podocin expression and ultrastructural injury. Transcriptomic analysis revealed enrichment of lipid metabolism-associated pathways, NF-?B signaling, and IL-17-related pathways. In HFD-fed mice, T cells displayed elevated SLAMF3 expression, while kidneys showed lipid accumulation, podocyte structural damage, and activation of IL-17RA/PI3K/NF-?B signaling. Importantly, blockade of IL-17 or genetic deletion of SLAMF3 in T cells significantly attenuated podocyte injury both in vitro and in vivo.

Conclusion

SLAMF3 upregulation on T cells links insulin resistance to podocyte injury through activation of the IL-17RA/PI3K/NF-?B pathway in DKD. Targeting SLAMF3 may represent a novel immunometabolic therapeutic strategy to prevent podocyte injury in diabetes.