Effect of iron restriction on renal damage and mineralocorticoid receptor signaling in a rat model of chronic kidney disease

Yoshiro Naito, Aya Fujii, Hisashi Sawada, Shinichi Hirotani, Toshihiro Iwasaku, Akiyo Eguchi, Mitsumasa Ohyanagi, Takeshi Tsujino, Tohru Masuyama

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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. CONCLUSION: Taken together, these data uncover a novel effect of iron restriction on renal damage and hypertension through the inhibition of renal mineralocorticoid receptor signaling.

Original languageEnglish
Pages (from-to)2192-2201
Number of pages10
JournalJournal of Hypertension
Volume30
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • chronic kidney disease
  • hypertension
  • iron
  • mineralocorticoid receptor
  • transferrin receptor 1

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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