57493 20200221144326.0 doi 10.1038/cddis.2015.392 sideral 96827 ART-2016-96827 eng Deuel, J.W. Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response 2016 Access copy available to the general public Unrestricted 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. info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 5.965 2016 CELL BIOLOGY 39 / 189 = 0.206 2016 Q1 T1 2.737 2016 Cancer Research 2016 Q1 Cell Biology 2016 Q1 Medicine (miscellaneous) 2016 Q1 Immunology 2016 Q1 Cellular and Molecular Neuroscience 2016 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Schaer, C.A. Boretti Opitz, L. (orcid)0000-0002-1827-1250 Garcia-Rubio, I. Baek, J.H. Spahn, D.R. Buehler, P.W Schaer, D.J. 7, 1 (2016), e2064 [12 pp.] Cell death dis. Cell death & disease 2041-4889 2762629 http://zaguan.unizar.es/record/57493/files/texto_completo.pdf Versión publicada 134833 http://zaguan.unizar.es/record/57493/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:57493 articulos driver 2020-02-21-13:44:12 ARTICLE