TRAIL deficiency contributes to diabetic nephropathy in fat-fed ApoE-/- mice

Siân P Cartland; Jonathan H Erlich; Mary M Kavurma

doi:10.1371/journal.pone.0092952

TRAIL deficiency contributes to diabetic nephropathy in fat-fed ApoE-/- mice

PLoS One. 2014 Mar 25;9(3):e92952. doi: 10.1371/journal.pone.0092952. eCollection 2014.

Authors

Siân P Cartland¹, Jonathan H Erlich², Mary M Kavurma³

Affiliations

¹ Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia.
² Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
³ Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia; Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia.

Abstract

Background: We recently demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is protective of diet-induced diabetes in mice. While TRAIL has been implicated in chronic kidney disease, its role in vivo in diabetic nephropathy is not clear. The present study investigated the role of TRAIL in the pathogenesis of diabetic nephropathy using TRAIL(-/-)ApoE(-/-) mice.

Methods: TRAIL(-/-)ApoE(-/-) and ApoE(-/-) mice were fed a high fat diet for 20 w. Plasma glucose and insulin levels were assessed over 0, 5, 8 and 20 w. At 20 w, markers of kidney function including creatinine, phosphate, calcium and cystatin C were measured. Changes in mRNA expression of MMPs, TIMP-1, IL-1β and IL-18 were assessed in the kidney. Functional and histological changes in kidneys were examined. Glucose and insulin tolerance tests were performed.

Results: TRAIL(-/-)ApoE(-/-) mice had significantly increased urine protein, urine protein:creatinine ratio, plasma phosphorous, and plasma cystatin C, with accelerated nephropathy. Histologically, increased extracellular matrix, mesangial expansion and mesangial cell proliferation in the glomeruli were observed. Moreover, TRAIL(-/-)ApoE(-/-) kidneys displayed loss of the brush border and disorganisation of tubular epithelium, with increased fibrosis. TRAIL-deficient kidneys also had increased expression of MMPs, TIMP-1, PAI-1, IL-1β and IL-18, markers of renal injury and inflammation. Compared with ApoE(-/-) mice, TRAIL-/-ApoE-/- mice displayed insulin resistance and type-2 diabetic features with reduced renal insulin-receptor expression.

Conclusions: Here, we show that TRAIL-deficiency in ApoE(-/-) mice exacerbates nephropathy and insulin resistance. Understanding TRAIL signalling in kidney disease and diabetes, may therefore lead to novel strategies for the treatment of diabetic nephropathy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoproteins E / deficiency*
Biomarkers / metabolism
Cytokines / genetics
Diabetes Mellitus, Type 2 / complications
Diabetic Nephropathies / etiology*
Diabetic Nephropathies / genetics
Diabetic Nephropathies / metabolism*
Diabetic Nephropathies / pathology
Diet, High-Fat / adverse effects*
Fibrosis
Gene Expression Regulation
Insulin / metabolism
Male
Mice
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand / deficiency*

Substances

Apolipoproteins E
Biomarkers
Cytokines
Insulin
TNF-Related Apoptosis-Inducing Ligand

Grants and funding

MMK is supported by a Heart Foundation Career Development Fellowship (CR 12S 6833). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.