title: Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease.
abstract: OBJECTIVE
  Iron is associated with the pathogenesis of chronic kidney disease (CKD). Activation of mineralocorticoid receptor signaling is implicated in CKD; however, a link between iron and mineralocorticoid receptor signaling in CKD remains unknown. We have previously shown that long-term dietary iron restriction leads to increased sodium and decreased potassium excretions in the rat urine. Herein, we investigated the effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of CKD.
  
  
  METHODS
  CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. CKD rats were divided into untreated and dietary iron-restricted groups.
  
  
  RESULTS
  CKD rats exhibited proteinuria, glomerulosclerosis, tubulointerstitinal damage, and podocyte injury. In contrast, these changes were attenuated by 16 weeks of iron-restricted diet. Consistent with these findings, iron restriction suppressed increased gene expression of collagen type III, transforming growth factor-β, CD68, and tumor necrosis factor-α in the CKD kidney. Importantly, increased expression of nuclear mineralocorticoid receptor and SGK1, a key downstream effector of mineralocorticoid receptor signaling, in the CKD kidney was markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1, and divalent metal transporter 1 was increased in the CKD renal tubules, along with increased iron accumulation, superoxide production, and urinary iron excretion. CKD rats also developed hypertension, although iron restriction suppressed the development of hypertension.
  
  
  CONCLUSIONS
  Taken together, these data uncover a novel effect of iron restriction on renal damage and hypertension through the inhibition of renal mineralocorticoid receptor signaling.
authors.affiliation: Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan. ynaito@hyomed.ac.jp
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Naito
authors.forename: Aya
authors.initials: A
authors.lastname: Fujii
authors.forename: Hisashi
authors.initials: H
authors.lastname: Sawada
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Iwasaku
authors.forename: Akiyo
authors.initials: A
authors.lastname: Eguchi
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Ohyanagi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsujino
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D017874:Immediate-Early Proteins / Q000235:genetics; D007501:Iron / Q000378:metabolism; D019266:Iron, Dietary / Q000008:administration & dosage*; D008297:Male; D009392:Nephrectomy; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D027682:Cation Transport Proteins; D006419:Heme Oxygenase (Decyclizing); D017874:Immediate-Early Proteins; D007501:Iron; D019266:Iron, Dietary; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases; C491523:Hmox1 protein, rat