title: Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis.
abstract: Chronic iron (Fe) overload is associated with a marked increase in renal tissue iron content and injury. It is estimated that 10% of the American population carry the gene for hemochromatosis and 1% actually suffer from iron overload. The mechanism of iron overload-associated renal damage has not been fully elucidated. Iron can accelerate lipid peroxidation leading to organelle membrane dysfunction and subsequent cell injury/death. Iron-catalyzed generation of reactive oxygen species (ROS) is responsible for initiating the peroxidatic reaction. We investigated the possible association of oxidative stress and its impact on nitric oxide (NO) metabolism in iron-overload-associated renal injury. Rats were randomized into Fe-loaded (given 0.5 g elemental iron/kg body weight as iron dextran; i.v.), Fe-depleted (given an iron-free diet for 20 weeks), and control groups. Renal histology, tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS), renal tissue expression of nitrotyrosine, plasma, and renal tissue lipid peroxidation product, malondialdehyde (MDA), and plasma and urinary NO metabolites (NOx) were examined. Iron overload was associated with mild proteinuria, tissue iron deposition together with significant glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Rare focal glomerulosclerosis and tubulointerstitial changes were noted in normal controls. No renal lesions were observed in Fe-depleted rats. Iron deposits were seen in glomeruli, proximal tubules, and interstitium. The iron staining in the distal tubules was negligible. Both plasma and renal tissue MDA and renal tissue nitrotyrosine were increased significantly in Fe-loaded rats compared with control rats. In contrast, Fe-depleted animals showed a marked reduction in plasma and renal tissue MDA and nitrotyrosine together with significant elevation of urinary NOx excretion. In addition, iron-overload was associated with up-regulation of renal eNOS and iNOS expressions when compared with the control and Fe-depleted rats that showed comparable values. In conclusion, chronic iron overload resulted in iron deposition in the glomeruli and proximal tubules with various renal lesions and evidence of increased ROS activity, enhanced ROS-mediated inactivation, and sequestration of NO and compensatory up-regulation of renal eNOS and iNOS expressions. However, iron depletion was associated with reduced MDA and tissue nitrotyrosine abundance, increased urinary NOx excretion, normal nitric oxide synthase (NOS) expression, and absence of renal injury. These findings point to the possible role of ROS in chronic iron overload-induced renal injury.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75390-9073, USA. joseph.zhou@utsouthwestern.edu
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Z
authors.initials: Z
authors.lastname: Laszik
authors.forename: X Q
authors.initials: XQ
authors.lastname: Wang
authors.forename: F G
authors.initials: FG
authors.lastname: Silva
authors.forename: N D
authors.initials: ND
authors.lastname: Vaziri
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D005609:Free Radicals / Q000378:metabolism; D006486:Hemosiderosis / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007501:Iron / Q000032:analysis / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D037102:Lectins; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009566:Nitrates / Q000097:blood / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005609:Free Radicals; D037102:Lectins; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D008315:Malondialdehyde; D007501:Iron; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat