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

Area of Science:

• Nephrology
• Cell Biology
• Molecular Medicine

Background:

• Diabetic kidney disease (DKD) is a leading cause of kidney failure, characterized by podocyte injury and loss.
• Podocyte cell death, including PANoptosis (apoptosis, pyroptosis, and necroptosis), contributes to DKD progression.

Purpose of the Study:

• To investigate the role of Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its receptor, Death Receptor 5 (DR5), in podocyte injury in DKD.
• To explore the therapeutic potential of targeting the TRAIL/DR5 pathway in DKD.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of human kidney samples to compare normal and DKD tissues.
• In vitro studies using cultured human podocytes treated with TNF-α, TRAIL, or DR5 activators/inhibitors.
• In vivo studies involving genetically modified mice with podocyte-specific deletion or overexpression of TNFSF10/TNFRSF10B, and treatment with DR5 inhibitors.

Main Results:

• Increased expression of TRAIL (TNFSF10) and DR5 (TNFRSF10B) was observed in podocytes from DKD patients and correlated with disease severity.
• TNF-α stimulation upregulated TRAIL and DR5 in cultured podocytes, promoting PANoptosis.
• Inhibition of TRAIL or DR5 alleviated podocyte PANoptosis in vitro, while their activation enhanced it.
• Podocyte-specific deletion of TNFSF10 or TNFRSF10B protected against kidney injury in mouse models of DKD.
• Overexpression of TNFSF10 in podocytes exacerbated DKD phenotypes, and DR5 inhibition reduced albuminuria and glomerular injury.

Conclusions:

• The TRAIL/DR5 signaling pathway plays a critical autocrine role in mediating podocyte injury and PANoptosis in DKD.
• Targeting the TRAIL/DR5 axis represents a promising therapeutic strategy for managing DKD and preventing kidney failure.