PLoS One. 2014 Mar 25;9(3):e92952.

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

Cartland SP1, Erlich JH2, Kavurma MM3.
  • 1Centre for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia; The Heart Research Institute, Sydney, New South Wales, Australia.
  • 2Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
  • 3Centre 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.



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.

PMID: 24667560



TNF-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily cytokine that can promote both apoptosis and survival of cells. TRAIL exists in both membrane-bound and soluble forms; on binding its receptors it can rapidly induce apoptosis in cancer cells, but can also activate nuclear factor-kB (NF-kB), mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and Akt, leading to increased expression of genes involved in survival of normal cells. The non-apoptotic actions of TRAIL are yet to be fully investigated.

Diabetes is not only a risk factor for atherosclerosis, but also diabetic nephropathy (DN), the leading cause of end-stage renal disease that results in the morbidity and mortality of diabetic patients. We have previously demonstrated a novel protective function for TRAIL in cardiovascular disease (CVD) and diabetes, here we wanted to assess whether

TRAIL was protective or promoted the pathogenesis of DN. Using our unique murine models, we established that TRAIL-gene deletion in ApoE-/- mice resulted in features of DN after 20 weeks of high fat diet feeding. TRAIL-/-ApoE-/- mice had impaired glucose clearance and insulin tolerance, associated with accelerated renal injury manifested by increased plasma and urine biomarkers of renal injury. Histopathological evidence of renal injury supported our findings. More inflammation and fibrosis was observed in TRAIL-deficient kidneys.

Chronic kidney disease and diabetes are associated with accelerated atherosclerosis. Correspondingly, TRAIL deletion in ApoE-/- mice led to an increase in atherosclerotic lesion size with reduced smooth muscle in the brachiocephalic artery (Figure 1). Notably, the lesions in the TRAIL-deficient animals were less cellular than the control ApoE-/- arteries.

Our results confirm that TRAIL plays an important protective role in diabetes, atherosclerosis and DN. Understanding how this molecule protects against disease may help develop new strategies for the treatment or complications associated with diabetes and CVD .


f1Figure 1: TRAIL-deficiency promotes larger atherosclerotic lesion size. Left panel, Haemotoxylin and eosin (H&E) staining of brachiocephlic arteries of 20 w high fat diet-fed TRAIL-/-ApoE-/- and ApoE-/- mice. Quantification of plaque area was measured by Image J. Left panel, smooth muscle a-actin (SMA) staining of brachiocephalic arteries. TRAIL-deficient arteries have reduced SMA staining compared to control arteries. Results are mean ± SEM; n=6-8; *p < 0.05.


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