Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice

Yasumasa Ikeda,Koichiro Tsuchiya,Yoshito Zamami,Hirofumi Hamano,Masaki Imanishi,Tasuku Hirayama,Kenshi Takechi,Keisuke Ishizawa,Ken-Ichi Aihara,Yuya Horinouchi,Yuki Izawa-Ishizawa,Toshiaki Tamaki,Hideko Nagasawa,Licht Miyamoto,Seiji Kishi

doi:10.1038/s41598-017-11089-0

Yasumasa Ikeda, Koichiro Tsuchiya + Show 13 more

Open Access

https://doi.org/10.1038/s41598-017-11089-0

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Abstract

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.

Highlights

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD)
Renal tubulointerstitial injury was induced in mice with bovine serum albumin (BSA) overload, and it was alleviated by dietary iron restriction (Fig. 1a and b)
The mRNA expression of lipocalin-2, a marker of tubulointerstitial damage, was upregulated in BSA-overload mice, which was inhibited by iron-restricted diet (IRD, Fig. 1c)

Summary

Introduction

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domaincontaining protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury. In different experimental animal models, iron is involved in determining the pathological condition of CKD such as diabetic nephropathy[12,13,14], hypertensive kidney injury[15, 16], and renal fibrosis[17], and these diseases are ameliorated by iron reduction in the body. We determined that dietary iron restriction alleviates protein overload-induced tubulointerstitial injury, and inhibits oxidative stress and inflammatory changes in mice. Ferrous iron production is elevated in the kidneys with protein overload, suggesting its involvement in the pathological condition of protein-overload renal injury through oxidative stress via the Fenton reaction

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