000057493 001__ 57493
000057493 005__ 20200221144326.0
000057493 0247_ $$2doi$$a10.1038/cddis.2015.392
000057493 0248_ $$2sideral$$a96827
000057493 037__ $$aART-2016-96827
000057493 041__ $$aeng
000057493 100__ $$aDeuel, J.W.
000057493 245__ $$aHemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response
000057493 260__ $$c2016
000057493 5060_ $$aAccess copy available to the general public$$fUnrestricted
000057493 5203_ $$aIntravascular 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.
000057493 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000057493 590__ $$a5.965$$b2016
000057493 591__ $$aCELL BIOLOGY$$b39 / 189 = 0.206$$c2016$$dQ1$$eT1
000057493 592__ $$a2.737$$b2016
000057493 593__ $$aCancer Research$$c2016$$dQ1
000057493 593__ $$aCell Biology$$c2016$$dQ1
000057493 593__ $$aMedicine (miscellaneous)$$c2016$$dQ1
000057493 593__ $$aImmunology$$c2016$$dQ1
000057493 593__ $$aCellular and Molecular Neuroscience$$c2016$$dQ1
000057493 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000057493 700__ $$aSchaer, C.A.
000057493 700__ $$aBoretti
000057493 700__ $$aOpitz, L.
000057493 700__ $$0(orcid)0000-0002-1827-1250$$aGarcia-Rubio, I.
000057493 700__ $$aBaek, J.H.
000057493 700__ $$aSpahn, D.R.
000057493 700__ $$aBuehler, P.W
000057493 700__ $$aSchaer, D.J.
000057493 773__ $$g7, 1 (2016), e2064 [12 pp.]$$pCell death dis.$$tCell death & disease$$x2041-4889
000057493 8564_ $$s2762629$$uhttps://zaguan.unizar.es/record/57493/files/texto_completo.pdf$$yVersión publicada
000057493 8564_ $$s134833$$uhttps://zaguan.unizar.es/record/57493/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000057493 909CO $$ooai:zaguan.unizar.es:57493$$particulos$$pdriver
000057493 951__ $$a2020-02-21-13:44:12
000057493 980__ $$aARTICLE