title: Eicosapentaenoic acid restores diabetic tubular injury through regulating oxidative stress and mitochondrial apoptosis.
abstract: The present study was designed to elucidate a possible mechanism of hyperglycemia-induced tubular injury and to examine a therapeutic potential of dietary eicosapentaenoic acid (EPA) for the prevention of diabetic kidney disease. Utilizing streptozotocin-induced diabetic mice, the extents of albuminuria and histological injuries were monitored at 2 wk after diabetic induction. Reactive oxygen species (ROS) production, apoptosis, and hypoxia in the kidney were evaluated by immunohistochemistry and Western blotting. An in vitro study was performed using rat proximal tubular cells (NRK-52E) to confirm the protective effect of EPA for methylglyoxal (MG)-induced ROS generation and staurosporine (STS)-induced mitochondrial apoptosis. The extents of albuminuria and histological tubular injuries were significantly lower in EPA-treated diabetic mice compared with untreated diabetic mice. The levels of lipid peroxidation product (4-hydroxy-2-nonenal), oxidative DNA damage (8-hydoxy-deoxyguanosine), and mitochondrial apoptosis (TUNEL, caspase-9, cleaved caspase-3, and cytochrome c release) in the tubular cells were also significantly lower in EPA-treated diabetic mice. Furthermore, hypoxia-inducible factor (HIF)-1α expression was significantly upregulated in the kidney tissues from EPA-treated mice compared with untreated diabetic mice. MG-induced ROS overproduction and STS-induced mitochondrial apoptosis in NRK-52E cells were significantly reduced by EPA treatment in vitro. These results indicated that the ROS generation and mitochondrial apoptosis were involved in hyperglycemia-induced tubular injury and EPA had a beneficial effect by suppressing ROS generation and mitochondrial apoptosis partly through augmentation of an HIF-1α response in diabetic kidney disease.
authors.affiliation: Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Sekiko
authors.initials: S
authors.lastname: Taneda
authors.forename: Kazuho
authors.initials: K
authors.lastname: Honda
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tomidokoro
authors.forename: Kenta
authors.initials: K
authors.lastname: Uto
authors.forename: Kosaku
authors.initials: K
authors.lastname: Nitta
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D015118:Eicosapentaenoic Acid / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007684:Kidney Tubules / Q000187:drug effects*; D015227:Lipid Peroxidation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D015118:Eicosapentaenoic Acid