TRAIL treatment prevents renal morphological changes and TGF-β-induced mesenchymal transition associated with...

Area of Science:

• Endocrinology
• Nephrology
• Cell Biology

Background:

• TNF-related apoptosis-inducing ligand (TRAIL) is explored for anti-cancer and diabetes treatment.
• Previous studies indicated TRAIL improves glucose control in animal models of diabetes.
• The effects of TRAIL in severe type 2 diabetes with nephropathy remain unclear.

Purpose of the Study:

• To evaluate the effects of TRAIL in a severe form of type 2 diabetes with nephropathy.
• To investigate TRAIL's impact on glucose control, kidney function, and fibrotic markers.
• To explore the underlying mechanisms of TRAIL's renoprotective actions.

Main Methods:

• db/db mice were treated with saline or TRAIL for 12 weeks.
• Renal tubular epithelial cells were cultured with TGF-β1, with or without TRAIL, DR5, and leptin receptor silencing.
• Assessment of glucose control, kidney morphology, function, inflammatory markers, and autophagy markers.

Main Results:

• TRAIL did not improve glucose control but reduced circulating IL-6 and resistin.
• TRAIL ameliorated glomerular and tubular morphology and improved kidney function, without affecting proteinuria.
• In vitro, TRAIL binding to DR5 rescued tubular cell morphology, increased E-cadherin, and reduced α-SMA expression, while reducing p62 accumulation.
• Both in vivo and in vitro, TRAIL reduced the accumulation of the autophagy substrate p62.

Conclusions:

• TRAIL demonstrates protective effects against organ damage in severe type 2 diabetes, independent of glucose control.
• TRAIL exhibits promising anti-fibrotic actions, potentially through the rescue of autophagy.
• These findings suggest TRAIL as a potential therapeutic agent for diabetic nephropathy.