The role of tubular iron accumulation in the remnant kidney.
Iron has been implicated in the pathophysiology of several models of acute and chronic renal disease. In this study, energy-dispersive x-ray spectrometry was used to quantify and localize iron in rat remnant kidneys (RK) and normal kidneys (NK) and to determine its pathophysiologic significance. Substantial iron accumulation occurred in proximal tubular cell secondary lysosomes of RK (P < 0.001 versus NK) and reached a plateau at 8 wk after partial nephrectomy. In NK, minor increases of iron also occurred with aging (P < 0.02). Proximal tubular iron accumulation correlated independently with protein excretion (r = 0.90) and impairment of GFR (r = 0.70) and was associated with tubular damage and phosphate accumulation (both P < 0.001). Iron nitrilotriacetate (1 mg/kg ip) increased tubular lysosomal iron accumulation and tubular damage (P < 0.001 versus nitrilotriacetate) in NK, comparable to levels seen in untreated RK, and increased cortical cytosolic malondialdehyde, consistent with reactive oxygen species generation. The iron chelator deferoxamine (30 mg/kg per day ip) significantly reduced iron accumulation and tubular damage in RK at 4 wk, compared with deferoxamine chelated to iron and untreated RK. These results suggest that filtered iron enters the remnant tubular lysosomes across the brush border membrane by endocytosis and may produce tubular damage in chronic renal disease by the generation of reactive oxygen species.
Department of Renal Medicine, Westmead Hospital, Sydney, Australia.
B J
BJ
Nankivell
J
J
Chen
R A
RA
Boadle
D C
DC
Harris
D000818:Animals; D003404:Creatinine / Q000378:metabolism; D003676:Deferoxamine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004577:Electron Probe Microanalysis; D005290:Ferric Compounds / Q000633:toxicity; D007238:Infarction / Q000378:metabolism; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000098:blood supply / Q000737:chemistry*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009392:Nephrectomy / Q000009:adverse effects; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D014168:Transferrin / Q000652:urine
D005290:Ferric Compounds; D017382:Reactive Oxygen Species; D014168:Transferrin; D003404:Creatinine; D007501:Iron; D003676:Deferoxamine; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate