Hepcidin Bound to α2-Macroglobulin Reduces Ferroportin-1 Expression and Enhances Its Activity at Reducing Serum Iron Levels

Huang, Michael L.H.; Austin, Christopher; Sari, Marie-Agnès; Rahmanto, Yohan Suryo; Ponka, Prem; Vyoral, Daniel; Richardson, Des R.

doi:10.1074/jbc.m113.471573

Cited by 22 publications

(19 citation statements)

References 62 publications

(112 reference statements)

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“…However, because samples were only at room temperature for approximately 8 h during sample set preparation, the contribution to isoform formation was likely negligible. Furthermore, it is unclear whether measurement procedures measure free hepcidin or hepcidin bound to ␣2-macroglobulin, which might contribute to heterogeneity to an unknown extent (23)(24)(25). Regardless of the cause of heterogeneity, it can only be reduced by assay modification, not by harmonization.…”

Section: Current Equivalence Between Measurement Proceduresmentioning

confidence: 99%

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

Vorm¹,

Hendriks

Laarakkers³

et al. 2016

Clinical Chemistry

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Section: Current Equivalence Between Measurement Proceduresmentioning

confidence: 99%

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

Vorm¹,

Hendriks

Laarakkers³

et al. 2016

Clinical Chemistry

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“…10,11 The (unbound) hepcidin is freely filtered across the glomerular membrane, which was shown in two murine studies in which radiolabeled human hepcidin (hhep) was administered intraperitoneally and intravenously and measured in urine. 12,13 Indeed, plasma hepcidin levels were increased compared with baseline after CABG, which may have contributed to the elevated urinary hepcidin levels observed in these patients. However, plasma hepcidin levels were not associated with development of AKI.…”

mentioning

confidence: 96%

Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin–Mediated Kidney Injury

Swelm

Wetzels

Verweij

et al. 2016

JASN

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Urinary hepcidin may have protective effects against AKI. However, renal handling and the potential protective mechanisms of hepcidin are not fully understood. By measuring hepcidin levels in plasma and urine using mass spectrometry and the kidney using immunohistochemistry after intraperitoneal administration of human hepcidin-25 (hhep25) in C57Bl/6N mice, we showed that circulating hepcidin is filtered by the glomerulus and degraded to smaller isoforms detected in urine but not plasma. Moreover, hepcidin colocalized with the endocytic receptor megalin in proximal tubules, and compared with wild-type mice, megalin-deficient mice showed higher urinary excretion of injected hhep25 and no hepcidin staining in proximal tubules that lack megalin. This indicates that hepcidin is reaborbed in the proximal tubules by megalin dependent endocytosis. Administration of hhep25 concomitant with or 4 hours after a single intravenous dose of hemoglobin abolished hemoglobin-induced upregulation of urinary kidney injury markers (NGAL and KIM-1) and renal Interleukin-6 and Ngal mRNA observed 24 hours after administration but did not affect renal ferroportin expression at this point. Notably, coadministration of hhep25 and hemoglobin but not administration of either alone greatly increased renal mRNA expression of hepcidin-encoding Hamp1 and hepcidin staining in distal tubules. These findings suggest a role for locally synthesized hepcidin in renal protection. Our observations did not support a role for ferroportin in hhep25-mediated protection against hemoglobin-induced early injury, but other mechanisms of cellular iron handling may be involved. In conclusion, our data suggest that both systemically delivered and locally produced hepcidin protect against hemoglobin-induced AKI.

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“…The recent study by Huang et al showed that serum iron levels are reduced to a significantly greater extent in mice treated with α 2 -macroglobulin-hepcidin complex than in those treated with unbound hepcidin. The researchers suggested that this binding delays hepcidin excretion by the kidney and increases its circulatory half-life and efficacy compared to free hepcidin (unbound 125 I-hepcidin was significantly increased in the kidney and urine relative to 125 I-hepcidin complexed to α 2 -macroglobulin) ( 8 ).…”

Section: Physiology Of Hepcidinmentioning

confidence: 99%

“…Up to 90% of circulating hepcidin is bound to α 2 -macroglobulin, and this complex was shown to reduce iron concentrations to a significantly greater extent than free hepcidin. It is argued that the reason is slower hepcidin urine excretion, but this remains to be confirmed in humans ( 8 ). In renal transplant recipients this could be of great significance, since their renal excretion is limited by graft function.…”

Section: Final Considerationsmentioning

confidence: 99%

Laboratory use of hepcidin in renal transplant recipients

Šimetić

Zibar

2016

Biochem Med

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Hepcidin is a small peptide with a critical role in cellular iron homeostasis, as it regulates utilization of stored iron and antimicrobial defense in inflammation (bacterial and fungal). Since it was isolated in 2000, and especially in the last decade, numerous studies aimed to evaluate the clinical use of plasma and urine hepcidin as a marker of anemia, especially anemia of chronic disease and post-transplant anemia (PTA). Hepcidin regulation is delicately tuned by two inflammatory pathways activated by interleukin-6 (IL-6) and bone morphogenic proteins (BMPs) and iron regulated pathway sensitive to circulating transferin-iron (TR-Fe) complex. BMP-mediated pathway and TR-Fe sensitive pathway seem to be connected by hemojuveline, a BMP co-factor that interacts with transferine receptor 2 (TRF2) in cases of high TR-Fe circulatory concentration. In addition to these regulatory mechanisms other regulators and signaling pathways are being extensively researched. Hepcidin has been identified as an important contributor to morbidity and mortality in end stage renal disease (ESRD) but no such association has jet been found in case of PTA. However, there is an association between higher doses of erythropoiesis-stimulating agents (ESA) and mortality in the posttransplant period and the assumption that hepcidin might play a role in ESA resistance in PTA. Thus the review’s main goal was to summarize papers published on the association of hepcidin with PTA, give up-to-date information on hepcidin regulation and on potential therapeutics that optimize hepcidin regulation. We also compared the performances of tests for hepcidin determination and reviewed research on immunosuppressants’ (IS) effect on hepcidin concentration.

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Hepcidin Bound to α2-Macroglobulin Reduces Ferroportin-1 Expression and Enhances Its Activity at Reducing Serum Iron Levels

Cited by 22 publications

References 62 publications

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin–Mediated Kidney Injury

Laboratory use of hepcidin in renal transplant recipients

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