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

Journal of the American Society of Nephrology : JASN
Rachel P L van SwelmDorine W Swinkels

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 admi...Continue Reading

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Citations

Jan 10, 2019·American Journal of Physiology. Renal Physiology·Sanne E G van RaaijRachel P L van Swelm
Feb 10, 2019·Journal of the American Society of Nephrology : JASN·David E LeafSushrut S Waikar
May 12, 2018·Cell Death & Disease·Rachel P L van SwelmDorine W Swinkels
Feb 6, 2018·Canadian Journal of Kidney Health and Disease·Nora ChoiJulie Ho
Aug 25, 2020·Annals of Laboratory Medicine·Christian AlbertAnja Haase-Fielitz
Aug 29, 2019·Nature Reviews. Nephrology·Kristof Van AvondtSacha Zeerleder
Jun 28, 2019·Frontiers in Pharmacology·Yogesh ScindiaSundararaman Swaminathan
Aug 28, 2019·Pharmaceuticals·Laura E DiepeveenDorine W Swinkels
Sep 27, 2019·Nature Reviews. Nephrology·Rachel P L van SwelmDorine W Swinkels
Sep 27, 2019·Journal of the American Society of Nephrology : JASN·Shreyak Sharma, David E Leaf
Jun 27, 2019·Pharmaceuticals·József BallaAbolfazl Zarjou
Oct 27, 2016·European Journal of Clinical Investigation·Michele F EisengaCarlo A J M Gaillard
Feb 7, 2021·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Richard A ZagerRenibus Therapeutics
Feb 16, 2021·Frontiers in Immunology·Oluwabukola T GbotoshoGregory J Kato
May 24, 2020·Kidney International·Yogesh ScindiaSundararaman Swaminathan
Apr 19, 2020·Seminars in Nephrology·Kayla McCullough, Subhashini Bolisetty
Apr 30, 2021·Frontiers in Medicine·Ewa WlazloYogesh Scindia
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Aug 8, 2021·International Journal of Molecular Sciences·József Balla, Abolfazl Zarjou
Sep 8, 2018·Journal of Proteome Research·Mario NavarreteJohn A Wilkins
Aug 28, 2021·International Journal of Molecular Sciences·Christina MertensMichaela Jung

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