TRAIL induces podocyte PANoptosis via death receptor 5 in diabetic kidney disease.

Podocytes can undergo PANoptosis (apoptosis, pyroptosis, and necroptosis). Diabetic kidney disease (DKD) is the leading cause of kidney failure, and podocyte loss is a major event leading to the progression of DKD. Here, we compared single cell RNA sequencing (scRNA-seq) data between three normal and three DKD human kidney samples and found a significant increase of TNFSF10 and TNFRSF10B expression in podocytes of patients with DKD. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), coded by TNFSF10, belongs to the TNF superfamily members and TNFRSF10B codes for death receptor 5 (DR5). We confirmed that expression of TRAIL and DR5 increased in podocytes of patients with DKD and correlated with the severity of DKD. In vitro, TNF-α stimulated TRAIL and DR5 expression in cultured human podocytes. Silence of TRAIL or DR5 by small interfering RNA alleviated TNF-α-stimulated podocytes PANoptosis, while overexpression of TRAIL, treatment with recombinant human TRAIL (rh-TRAIL) or the DR5 activator (Bioymifi) enhanced podocytes PANoptosis. In vivo, podocyte-specific deletion of TNFSF10 or TNFRSF10B alleviated podocyte and glomerular injury in high fat diet and streptozotocin-induced obese diabetic mice and was associated with decreased podocyte PANoptosis. Conversely, the induction of TNFSF10 overexpression specifically in podocytes exacerbated albuminuria and kidney injury in diabetic mice with increased podocyte PANoptosis. Additionally, administration of soluble DR5-Fc, an inhibitor of DR5, resulted in a marked reduction in albuminuria and glomerular injury in BTBR ob/ob mice. Our findings suggest a critical autocrine role of TRAIL/DR5 in inducing podocyte injury in DKD via activation of PANoptosis.