title: Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin-Mediated Kidney Injury.
abstract: 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.
authors.affiliation: Departments of Laboratory Medicine, Pharmacology and Toxicology, Rachel.vanSwelm@radboudumc.nl.
authors.forename: Rachel P L
authors.initials: RP
authors.lastname: van Swelm
authors.affiliation: Nephrology, and.
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.affiliation: Pharmacology and Toxicology.
authors.forename: Vivienne G M
authors.initials: VG
authors.lastname: Verweij
authors.affiliation: Departments of Laboratory Medicine.
authors.forename: Coby M M
authors.initials: CM
authors.lastname: Laarakkers
authors.affiliation: Pharmacology and Toxicology.
authors.forename: Jeanne C L M
authors.initials: JC
authors.lastname: Pertijs
authors.affiliation: Physiology, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Jenny
authors.initials: J
authors.lastname: van der Wijst
authors.affiliation: Institute of Physiology, Pathophysiology and Toxicology, Center for Biomedical Training and Research, University of Witten/Herdecke, Witten, Germany; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
authors.affiliation: Pharmacology and Toxicology, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands.
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.affiliation: Departments of Laboratory Medicine.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000517:prevention & control; D000818:Animals; D006454:Hemoglobins / Q000502:physiology*; D064451:Hepcidins / Q000378:metabolism* / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D006454:Hemoglobins; D064451:Hepcidins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C545475:hepcidin 25, human
keywords: acute kidney injury; hemoglobin; hepcidin; iron; megalin
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