Trans-resveratrol mitigates type 1 diabetes-induced oxidative DNA damage and accumulation of advanced glycation end products in glomeruli and tubules of rat kidneys

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Abstract

Hyperglycemia induces the formation of advanced glycation end products (AGEs) and their receptors (RAGEs), which alter several intracellular signaling mechanisms leading to the onset and progression of diabetic nephropathy. The present study focused on, i) modulatory effects of trans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) on structural changes, AGE (Nε-carboxymethyl-lysine), RAGE, oxidative stress and DNA damage, and apoptosis, and ii) localization of fibrotic changes, AGE, RAGE, 8-oxo-dG and 4-hydroxynonenal (4-HNE) in diabetic rat kidneys. Resveratrol (5 mg/kg; po, administered during last 45 days of 90-day-long hyperglycemic period) administration to streptozotocin-induced type 1 diabetic male Wistar rats reduced renal hypertrophy and structural changes (tubular atrophy, mesangial expansion or shrinkage, diffuse glomerulonephritis, and fibrosis), AGE accumulation, oxidative stress and DNA damage (8-oxo-dG), 4-HNE, caspase-3, and cleaved-caspase-3, but not the RAGE expression. The AGE accumulated in the mesangium, vascular endothelium, and proximal convoluted tubules and less intensely in distal convoluted tubules of diabetic rat kidneys. The RAGE expression increased in the convoluted tubules and collecting ducts of diabetic rat kidneys, but not in the mesangium. Diabetes increased the expression of 8-oxo-dG in nuclei and cytoplasm of renal cells, and 4-HNE in glomeruli, convoluted tubules, the loops of Henle and collecting ducts. Hyperglycemia-induced AGE-RAGE axis and oxidative stress in turn induced apoptosis in diabetic kidneys. Resveratrol mitigated all diabetic effects except the RAGE expression. In conclusion, Resveratrol significantly alleviates diabetes-induced glycation, oxidative damage, and apoptosis to inhibit the progression of diabetic nephropathy. Resveratrol supplementation may be useful to hinder the onset and progression of diabetic kidney diseases.

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