Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis

Chronic iron (Fe) overload is associated with a marked increase in renal ti ssue iron content and injury. It is estimated that 10% of the American popu lation carry the gene for hemochromatosis and 1% actually suffer from iron overload. The mechanism of iron overload-associated renal damage has not be en fully elucidated. Iron can accelerate lipid peroxidation leading to orga nelle 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 oxida tive 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; IV), Fe-depleted (given an i ron-free diet for 20 weeks), and control groups. Renal histology, tissue ex pression 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 met abolites (NOx) were examined. Iron overload was associated with mild protei nuria, 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 lesi ons were observed in Fe-depleted rats. Iron deposits were seen in glomeruli , proximal tubules, and interstitium. The iron staining in the distal tubul es was negligible. Both plasma and renal tissue MDA and renal tissue nitrot yrosine were increased significantly in Fe-loaded rats compared with contro l rats. In contrast, Fe-depleted animals showed a marked reduction in plasm a and renal tissue MDA and nitrotyrosine together with significant elevatio n of urinary NOx excretion. In addition, iron-overload was associated with up-regulation of renal eNOS and iNOS expressions when compared with the con trol and Fe-depleted rats that showed comparable values. In conclusion, chr onic iron overload resulted in iron deposition in the glomeruli and proxima l tubules with various renal lesions and evidence of increased ROS activity , enhanced ROB-mediated inactivation, and sequestration of NO and compensat ory up-regulation of renal eNOS and iNOS expressions. However, iron depleti on was associated with reduced MDA and tissue nitrotyrosine abundance, incr eased 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.