title: Plasma and urinary heme oxygenase-1 in AKI.
abstract: AKI induces upregulation of heme oxygenase 1 (HO-1), which exerts cytoprotective effects and modulates the renal response to injury, suggesting that a biomarker of intrarenal HO-1 activity may be useful. Because HO-1 largely localizes to the endoplasmic reticulum and has no known secretory pathway, it is unclear whether plasma or urinary levels of HO-1 reflect intrarenal HO-1 expression. We measured plasma and urinary levels of HO-1 by ELISA during the induction and/or maintenance phases of four mouse models of AKI: ischemia/reperfusion, glycerol-induced rhabdomyolysis, cisplatin nephrotoxicity, and bilateral ureteral obstruction. In addition, we measured levels of HO-1 mRNA and protein in the renal cortex. Each AKI model increased renal HO-1 gene expression, which corresponded with release of HO-1 into plasma and urine by 4 hours. Over time, the magnitudes of plasma and urinary HO-1 paralleled renal cortical gene expression. AKI and the associated uremia did not seem to affect extrarenal HO-1 gene activity assessed in the liver, lung, and spleen. In iron-challenged, cultured proximal tubule cells, we observed a positive correlation between HO-1 mRNA level and HO-1 release. In humans, 10 patients with AKI demonstrated markedly higher levels of plasma and urine HO-1 levels than 10 critically ill patients without AKI or 20 patients with CKD or ESRD. In summary, these data suggest that plasma and urinary HO-1 levels may serve as biomarkers of AKI and intrarenal HO-1 gene activity.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, WA 98109, USA. dzager@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Becker
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005990:Glycerol / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000097:blood* / Q000235:genetics / Q000652:urine*; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D012206:Rhabdomyolysis / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D005990:Glycerol; D002945:Cisplatin