TRAIL Deficiency Contributes to Diabetic Nephropathy in Fat-Fed ApoE^-/- Mice

<div><p>Background</p><p>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 <i>in vivo</i> in diabetic nephropathy is not clear. The present study investigated the role of TRAIL in the pathogenesis of diabetic nephropathy using TRAIL^-/-ApoE^-/- mice.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p>