TRAIL treatment prevents renal morphological changes and TGF-β-induced mesenchymal transition associated with diabetic nephropathy
Male
renal fibrosi
Epithelial-Mesenchymal Transition
renal fibrosis; TRAIL; type 2 diabetes
TRAIL
Kidney
Mice
03 medical and health sciences
Sequestosome-1 Protein
Animals
Humans
Diabetic Nephropathies
Gene Silencing
Inflammation
0303 health sciences
Body Weight
Feeding Behavior
renal fibrosis
Fibrosis
Rats
3. Good health
Receptors, TNF-Related Apoptosis-Inducing Ligand
Glucose
Kidney Tubules
Gene Expression Regulation
Receptors, Leptin
type 2 diabetes
Protein Binding
DOI:
10.1042/cs20201004
Publication Date:
2020-08-31T16:51:38Z
AUTHORS (8)
ABSTRACT
Abstract
Background: 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.
Materials and methods: 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.
Results: 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.
Conclusions: 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.
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CITATIONS (10)
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