title: Inducible NOS inhibition, eicosapentaenoic acid supplementation, and angiotensin II-induced renal damage.
abstract: BACKGROUND
  Cytochrome P450(CYP)-dependent hydroxylation and epoxygenation metabolites of arachidonic acid (AA) influence renal vascular tone, salt excretion, and inflammation. Transgenic rats over expressing both human renin and angiotensinogen genes (dTGR) feature angiotensin II (Ang II)-induced organ damage, increased expression of inducible nitric oxide synthase (iNOS), decreased AA hydroxylation, and epoxygenation. As nitric oxide production via iNOS can inhibit CYP AA metabolism, we tested the hypothesis that by blocking iNOS or by supplementing eicosapentanoic acid (EPA), which can serve as an alternative CYP substrate, Ang II-induced vasculopathy could be ameliorated.
  
  
  METHODS
  We treated dTGR with the iNOS inhibitor L-N(6)-(1-iminoethyl) lysine (L-NIL), EPA, and the combination of both treatments from week 4 to 7.
  
  
  RESULTS
  Immunohistochemistry showed that L-NIL and EPA reduced glomerular iNOS toward control levels. L-NIL-treated dTGR showed cardiac hypertrophy and albuminuria similar to untreated dTGR. EPA and the combination of EPA + L-NIL, ameliorated organ damage without lowering blood pressure. EPA and EPA + L-NIL reduced cardiac hypertrophy, albuminuria, renal fibronectin expression, and infiltration of monocytes/macrophages, compared to L-NIL and untreated dTGR. Reactive oxygen species were detected in glomeruli of untreated and L-NIL-treated dTGR, but was reduced in the EPA groups. EPA treatment reduced activator protein-1 (AP-1) activation and partially inhibited nuclear factor-kappaB (NF-kappaB) activity in kidneys of dTGR.
  
  
  CONCLUSIONS
  These results demonstrate that iNOS inhibition does not protect against Ang II-induced end-organ damage, while EPA treatment does. Our electromobility shift assay experiments revealed that EPA protection may involve inhibition of AP-1- and NF-kappaB-dependent pathways.
authors.affiliation: Medical Faculty of the Charité, Franz Volhard Clinic HELIOS Klinikum-Berlin, Berlin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Theuer
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Eva
authors.initials: E
authors.lastname: Kaergel
authors.forename: Horst
authors.initials: H
authors.lastname: Honeck
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D016718:Arachidonic Acid / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000808:Angiotensinogen; D000804:Angiotensin II; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D012083:Renin; D008239:Lysine