Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response

• DOI: 10.1038/cddis.2015.392
• Publication Date: 2016-01-21T16:03:54Z
• Authors: J W Deuel; C A Schaer; F S Boretti; L Opitz; I Garcia-Rubio; J H Baek; D R Spahn; P W Buehler; D J Schaer
• Keywords: Hemoglobinuria; Paroxysmal nocturnal hemoglobinuria

Abstract Intravascular hemolysis can result in hemoglobinuria with acute kidney injury. In this study we systematically explored two vivo animal models and a related cell culture system to identify hemoglobinuria-triggered damage pathways. of stored blood transfusion hemoglobin (Hb) exposure guinea pigs beagle dogs found that led intrarenal conversion ferrous Hb(Fe 2+ ) ferric 3+ ), accumulation free heme Hb-cross-linking products, enhanced 4-hydroxynonenal reactivity renal tissue, tubule These changes were associated activation cortex gene expression signature indicative oxidative stress the unfolded protein response (UPR). Tubule cells hemolytic animals demonstrated oxygenase heat shock injury-related neutrophil gelatinase-associated lipocalin. adverse completely prevented by haptoglobin treatment. The findings extrapolated MS-based proteome analysis SILAC-labeled epithelial exposed within concentration range estimate exposure. experiments confirmed is likely trigger barrier deregulation reinforced hypothesis uncontrolled could UPR as an important pathway injury during hemoglobinuria.