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dc.contributor.author
Deuel, Jeremy W.
dc.contributor.author
Schaer, Christian A.
dc.contributor.author
Boretti, Felicitas Schär
dc.contributor.author
Opitz, Lennart
dc.contributor.author
García-Rubio, Inés
dc.contributor.author
Baek, Jinhyen
dc.contributor.author
Spahn, Donat Rudolph
dc.contributor.author
Buehler, Paul W.
dc.contributor.author
Schaer, Dominik J.
dc.date.accessioned
2019-09-09T09:22:54Z
dc.date.available
2017-06-12T01:42:15Z
dc.date.available
2019-09-09T09:22:54Z
dc.date.issued
2016
dc.identifier.issn
2041-4889
dc.identifier.other
10.1038/cddis.2015.392
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/113540
dc.identifier.doi
10.3929/ethz-b-000113540
dc.description.abstract
Intravascular hemolysis can result in hemoglobinuria with acute kidney injury. In this study we systematically explored two in vivo animal models and a related cell culture system to identify hemoglobinuria-triggered damage pathways. In models of stored blood transfusion and hemoglobin (Hb) exposure in guinea pigs and beagle dogs we found that hemoglobinuria led to intrarenal conversion of ferrous Hb(Fe2+) to ferric Hb(Fe3+), accumulation of free heme and Hb-cross-linking products, enhanced 4-hydroxynonenal reactivity in renal tissue, and acute tubule injury. These changes were associated in guinea pigs with activation of a renal cortex gene expression signature indicative of oxidative stress and activation of the unfolded protein response (UPR). Tubule cells of hemolytic animals demonstrated enhanced protein expression of heme oxygenase and heat shock protein and enhanced expression of acute kidney injury-related neutrophil gelatinase-associated lipocalin. These adverse changes were completely prevented by haptoglobin treatment. The in vivo findings were extrapolated to a MS-based proteome analysis of SILAC-labeled renal epithelial cells that were exposed to free heme within a concentration range estimate of renal tubule heme exposure. These experiments confirmed that free heme is a likely trigger of tubule barrier deregulation and oxidative cell damage and reinforced the hypothesis that uncontrolled free heme could trigger the UPR as an important pathway of renal injury during hemoglobinuria.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2016-01-21
ethz.journal.title
Cell Death & Disease
ethz.journal.volume
7
en_US
ethz.pages.start
e2064
en_US
ethz.size
12 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.nebis
006029226
ethz.publication.place
London, UK
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung & Wirtschaftsbez. / Domain VP Research & Corporate Relations::02207 - Functional Genomics Center Zürich / Functional Genomics Center Zürich
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung & Wirtschaftsbez. / Domain VP Research & Corporate Relations::02207 - Functional Genomics Center Zürich / Functional Genomics Center Zürich
ethz.date.deposited
2017-06-12T01:42:32Z
ethz.source
ECIT
ethz.identifier.importid
imp593654299e4c799351
ethz.ecitpid
pub:175236
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-18T15:32:01Z
ethz.rosetta.lastUpdated
2019-09-09T09:23:06Z
ethz.rosetta.versionExported
true
ethz.COinS
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