title: Combination effects of enalapril and losartan on lipid peroxidation in the kidneys of KK-Ay/Ta mice.
abstract: BACKGROUND
  Adenosine monophosphate activated protein kinase (AMPK) has a protective effect on lipid peroxidation. Adiponectin and AMPK might have a role in the pathogenesis of diabetic nephropathy. Blockade of the renin-angiotensin system (RAS) increases adiponectin levels and reduces oxidative stress. The objective of the present study was to examine lipid peroxidation via adiponectin and AMPK activation in the kidneys of KK-A(y)/Ta mice by RAS inhibitors, such as enalapril and/or losartan.
  
  
  METHODS
  KK-A(y)/Ta mice were given enalapril (2.5 mg/kg/day) and/or losartan (25 mg/kg/day), or hydralazine (25 mg/kg/day) in the drinking water for 8 weeks starting at 8 weeks of age. They were divided into 5 groups as follows: enalapril 2.5 mg/kg/day treatment group (n = 5), losartan 25 mg/kg/day treatment group (n = 5), enalapril 2.5 mg/kg/day + losartan 25 mg/kg/day combination treatment group (n = 5), hydralazine 25 mg/kg/day treatment group (n = 5) and tap water group as the untreated group (n = 5). The urinary albumin/creatinine ratio (ACR), serum adiponectin and systemic blood pressure were measured as test parameters. Expressions of adiponectin, phospho-AMPKalpha (p-AMPKalpha) and phospho-acetyl CoA carboxylase(beta) (p-ACC(beta)) in the kidneys were evaluated by Western blot analyses. Pathological changes of glomeruli were evaluated by light microscopy. Accumulations of N(epsilon)-(carboxymethyl) lysine (CML), malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) in glomeruli were evaluated by immunohistochemical analyses.
  
  
  RESULTS
  Enalapril and/or losartan improved levels of urinary ACR with activation of adiponectin, p-AMPKalpha and p-ACC(beta) in the kidneys. CML, MDA and 4-HNE expressions in glomeruli were significantly suppressed by enalapril and/or losartan, especially in the combination treatment group.
  
  
  CONCLUSIONS
  It appears that enalapril and/or losartan, especially in combination, inhibited accumulation of CML/MDA/4-HNE in diabetic renal tissues. These effects might be related to lipid peroxidation via tissue-specific activation of adiponectin and AMPK.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Tomohito
authors.initials: T
authors.lastname: Gohda
authors.forename: Ikko
authors.initials: I
authors.lastname: Ohara
authors.forename: Shinji
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Maki
authors.initials: M
authors.lastname: Murakoshi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kaneko
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Aoki
authors.forename: Hitoe
authors.initials: H
authors.lastname: Toyoda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Funabiki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Horikoshi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D019808:Losartan