Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis

Cell Death & Disease
Rachel P L van SwelmDorine W Swinkels

Abstract

Hemoglobinuria is associated with kidney injury in various hemolytic pathologies. Currently, there is no treatment available and its pathophysiology is not completely understood. Here we studied the potential detrimental effects of hemoglobin (Hb) exposure to the distal nephron (DN). Involvement of the DN in Hb kidney injury was suggested by the induction of renal hepcidin synthesis (p < 0.001) in mice repeatedly injected with intravenous Hb. Moreover, the hepcidin induction was associated with a decline in urinary kidney injury markers 24p3/NGAL and KIM1, suggesting a role for hepcidin in protection against Hb kidney injury. We demonstrated that uptake of Hb in the mouse cortical collecting duct cells (mCCDcl1) is mediated by multi-protein ligand receptor 24p3R, as indicated by a significant 90% reduction in Hb uptake (p < 0.001) after 24p3R silencing. Moreover, incubation of mCCDcl1 cells with Hb or hemin for 4 or 24 h resulted in hepcidin synthesis and increased mRNA expression of markers for oxidative, inflammatory and ER stress, but no cell death as indicated by apoptosis staining. A protective role for cellular hepcidin against Hb-induced injury was demonstrated by aggravation of oxidative, inflammatory and ER stress afte...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
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Frank ThévenodMichael D Garrick
Sep 27, 2019·Nature Reviews. Nephrology·Rachel P L van SwelmDorine W Swinkels
Jan 25, 2021·Free Radical Biology & Medicine·Qinjie LiuJianan Ren
Apr 19, 2020·Seminars in Nephrology·Kayla McCullough, Subhashini Bolisetty
Apr 18, 2020·Cell Chemical Biology·Alexia BelavgeniAndreas Linkermann

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Methods Mentioned

BETA
FCS
PCR

Software Mentioned

Axiovision
GraphPad Prism

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis