title: Amelioration of renal injury and oxidative stress by the nNOS inhibitor L-VNIO in the salt-sensitive mRen2.Lewis congenic rat.
abstract: Salt sensitivity is a key risk factor for cardiovascular disease and renal injury. Alterations in renal nitric oxide may contribute to salt-dependent increases in blood pressure and tissue damage. Therefore, we assessed the expression of nitric oxide synthase (NOS) isoforms in the kidney and the effects of nNOS inhibition on renal injury, inflammation, and oxidative stress in the female mRen2.Lewis rat (mRen), a model of salt-sensitive hypertension. We find that a high-salt diet (4% sodium) significantly reduced endothelial NOS mRNA (2.6-fold) and protein (1.5-fold) but increased nNOS mRNA (2.4-fold) and protein (1.9-fold) in the renal cortex of these animals. Immunostaining for nNOS also seemed higher in macula densa and cortical tubules of the rats fed a high-salt diet. Circulating nitrate and nitrite levels were reduced, including the tissue levels of the NOS cofactor tetrahydrobiopterin. Cortical markers of oxidative stress (4HNE, 8-OH-deoxyguanosine) and fibrosis were increased; however, mRNA levels of the NAD(P)H oxidase components NOX4, p22phox, and p47phox were reduced. Chronic treatment with the nNOS inhibitor N-(1-Imino-3-butenyl)-L-ornithine did not influence systolic blood pressure after 4 weeks but significantly attenuated albuminuria, renal fibrosis, inflammation, and indices of oxidative stress. We conclude that an increase in nNOS expression in conjunction with reduced levels of cortical tetrahydrobiopterin may stimulate oxidative stress and renal injury in the salt-sensitive female mRen2.Lewis rat.
authors.affiliation: The Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1095, USA. lyamaley@wake-health.edu
authors.forename: Liliya M
authors.initials: LM
authors.lastname: Yamaleyeva
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lindsey
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
authors.forename: Li Li
authors.initials: LL
authors.lastname: Zhang
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gallagher
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012083:Renin / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: C111862:N(5)-(1-imino-3-butenyl)ornithine; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; C562214:mRen2 protein, rat; D001708:Biopterins; D009569:Nitric Oxide; D009952:Ornithine; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D012083:Renin; C003402:sapropterin