Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria

Eileen S Marks,Wei Fan,Erika I Boesen,Jered C Garrison,Susan K Brusnahan,Wenting Zhang,Mathilde L Bonnemaison

doi:10.1038/s41598-017-13029-4

Eileen S Marks, Wei Fan + Show 5 more

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https://doi.org/10.1038/s41598-017-13029-4

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Journal: Scientific Reports	Publication Date: Oct 9, 2017
Citations: 31	License type: open-access

Affiliation: University of Nebraska Medical Center

Abstract

Proteins involved in iron homeostasis have been identified as biomarkers for lupus nephritis, a serious complication of systemic lupus erythematosus (SLE). We tested the hypothesis that renal iron accumulation occurs and contributes to renal injury in SLE. Renal non-heme iron levels were increased in the (New Zealand Black x New Zealand White) F1 (NZB/W) mouse model of lupus nephritis compared with healthy New Zealand White (NZW) mice in an age- and strain-dependent manner. Biodistribution studies revealed increased transferrin-bound iron accumulation in the kidneys of albuminuric NZB/W mice, but no difference in the accumulation of non-transferrin bound iron or ferritin. Transferrin excretion was significantly increased in albuminuric NZB/W mice, indicating enhanced tubular exposure and potential for enhanced tubular uptake following filtration. Expression of transferrin receptor and 24p3R were reduced in tubules from NZB/W compared to NZW mice, while ferroportin expression was unchanged and ferritin expression increased, consistent with increased iron accumulation and compensatory downregulation of uptake pathways. Treatment of NZB/W mice with the iron chelator deferiprone significantly delayed the onset of albuminuria and reduced blood urea nitrogen concentrations. Together, these findings suggest that pathological changes in renal iron homeostasis occurs in lupus nephritis, contributing to the development of kidney injury.

Highlights

Lupus nephritis is a serious complication of the autoimmune disease systemic lupus erythematosus (SLE), affecting up to 50% percent of patients[1]
Renal iron accumulation occurs in the NZB/W mouse model of SLE
By 20 weeks of age, renal iron levels were beginning to diverge and were significantly elevated in albuminuric NZB/W mice aged 32–36 weeks compared to age-matched New Zealand White (NZW) mice, at which time ds DNA autoantibodies were strikingly elevated in the NZB/W mice

Summary

Introduction

Lupus nephritis is a serious complication of the autoimmune disease systemic lupus erythematosus (SLE), affecting up to 50% percent of patients[1]. Multiple proteins involved in iron homeostasis have been identified as urinary biomarkers of lupus nephritis or are increased in the urine of SLE patients with active disease. These include the iron-carrying proteins transferrin and neutrophil gelatinase associated lipocalin (NGAL or lipocalin-2)[3], the iron storage protein ferritin[4], ferroxidase enzyme ceruloplasmin[5,6], and hepcidin[7], which regulates gastrointestinal iron uptake and export of iron from cells. Increased circulating levels of ferritin have been found in SLE patients with active disease[4,8] These differences are noteworthy in that while iron is a key component of many proteins, disruption of iron homeostasis resulting in unbound redox active iron can promote cellular damage, apoptosis and ferroptosis via several mechanisms. Our experiments focused on female mice, consistent with the marked female sex-bias observed in the prevalence of SLE in human populations (90% female)[24]

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