title: Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress.
abstract: This study evaluated early renal functional, structural, and biochemical changes in high-calorie/high-fat diet fed mice, a model of prediabetes and alimentary obesity. Male C57BL6/J mice were fed normal (11 kcal% fat) or high-fat (58 kcal% fat) diets for 16 wk. Renal changes were evaluated by histochemistry and immunohistochemistry, Western blot analysis, ELISA, enzymatic assays, and chemiluminometry. High-fat diet consumption led to increased body and kidney weights, impaired glucose tolerance, hyperinsulinemia, polyuria, a 2.7-fold increase in 24-h urinary albumin excretion, 20% increase in renal glomerular volume, 18% increase in renal collagen deposition, and 8% drop of glomerular podocytes. It also resulted in a 5.3-fold increase in urinary 8-isoprostane excretion and a 38% increase in renal cortex 4-hydroxynonenal adduct accumulation. 4-hydroxynonenal adduct level and immunoreactivity or Sirtuin 1 expression in renal medulla were not affected. Studies of potential mechanisms of the high-fat diet induced renal cortex oxidative injury revealed that whereas nicotinamide adenine dinucleotide phosphate reduced form oxidase activity only tended to increase, 12/15-lipoxygenase was significantly up-regulated, with approximately 12% increase in the enzyme protein expression and approximately 2-fold accumulation of 12(S)-hydroxyeicosatetraenoic acid, a marker of 12/15-lipoxygenase activity. Accumulation of periodic acid-Schiff -positive material, concentrations of TGF-β, sorbitol pathway intermediates, and expression of nephrin, CAAT/enhancer-binding protein homologous protein, phosphoeukaryotic initiation factor-α, and total eukaryotic initiation factor-α in the renal cortex were indistinguishable between experimental groups. Vascular endothelial growth factor concentrations were reduced in high-fat diet fed mice. In conclusion, systemic and renal cortex oxidative stress associated with 12/15-lipoxygenase overexpression and activation is an early phenomenon caused by high-calorie/high-fat diet consumption and a likely contributor to kidney disease associated with prediabetes and alimentary obesity.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Shevalye
authors.forename: Sergey
authors.initials: S
authors.lastname: Lupachyk
authors.forename: Pierre
authors.initials: P
authors.lastname: Watcho
authors.forename: Roman
authors.initials: R
authors.lastname: Stavniichuk
authors.forename: Khaled
authors.initials: K
authors.lastname: Khazim
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
mesh_terms: D000821:Animal Feed; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000209:etiology*; D004032:Diet; D059305:Diet, High-Fat / Q000009:adverse effects*; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism; D018384:Oxidative Stress; D050199:Podocytes / Q000378:metabolism; D011236:Prediabetic State / Q000175:diagnosis / Q000209:etiology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase