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

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) has attracted attention not only as an anti-cancer agent, but also as a potential treatment for diabetes. Animal studies have shown that TRAIL delivery ameliorated glucose control in type 1 and type 2 diabetes. It is currently unknown whether TRAIL positive effects are maintained in more severe forms of type 2 diabetes, and whether they include renoprotection. Our study aimed at evaluating TRAIL effects in a severe form of type 2 diabetes with nephropathy. A total of 20 db/db mice were treated with saline or TRAIL twice per week for 12 weeks. In parallel, renal tubular epithelial cells were cultured with TGF-β1 in the presence and absence of TRAIL, with and without silencing TRAIL-specific receptor (DR5) and leptin receptor. TRAIL did not improve glucose control, but it significantly reduced circulating interleukin (IL)-6 and resistin. In the kidney, TRAIL treatment significantly ameliorated glomerular and tubular morphology with an improvement in kidney function, but no effect on proteinuria. Our in vitro studies on TGF-β1-treated cells, showed that by binding to DR5, TRAIL rescued normal tubular cell morphology, increasing E-cadherin and reducing α-smooth muscle actin (SMA) expression, with no effects on cell viability. Interestingly, both in vivo and in vitro, TRAIL reduced the accumulation of the autophagy substrate p62. Our data confirm TRAIL protective effects against organ damage and shed light on to promising anti-fibrotic actions, which are independent of glucose control. TRAIL anti-fibrotic actions might be due to the rescue of autophagy in diabetes.