title: Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure.
abstract: Tissue preconditioning, whereby various short-term stressors initiate organ resistance to subsequent injury, is well recognized. However, clinical preconditioning of the kidney for protection against acute kidney injury (AKI) has not been established. Here we tested whether a pro-oxidant agent, iron sucrose, combined with a protoporphyrin (Sn protoporphyrin), can induce preconditioning and protect against acute renal failure. Mice were pretreated with iron sucrose, protoporphyrin, cyanocobalamin, iron sucrose and protoporphyrin, or iron sucrose and cyanocobalamin. Eighteen hours later, ischemic, maleate, or glycerol models of AKI were induced, and its severity was assessed the following day (blood urea nitrogen, plasma creatinine concentrations; post-ischemic histology). Agent impact on cytoprotective gene expression (heme oxygenase 1, hepcidin, haptoglobin, hemopexin, α1-antitrypsin, α1-microglobulin, IL-10) was assessed as renal mRNA and protein levels. AKI-associated myocardial injury was gauged by plasma troponin I levels. Combination agent administration upregulated multiple cytoprotective genes and, unlike single agent administration, conferred marked protection against each tested model of acute renal failure. Heme oxygenase was shown to be a marked contributor to this cytoprotective effect. Preconditioning also blunted AKI-induced cardiac troponin release. Thus, iron sucrose and protoporphyrin administration can upregulate diverse cytoprotective genes and protect against acute renal failure. Associated cardiac protection implies potential relevance to both AKI and its associated adverse downstream effects.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; University of Washington, Seattle, Washington, USA. Electronic address: dzager@fredhutch.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Frostad
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000510:Alpha-Globulins / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005290:Ferric Compounds / Q000627:therapeutic use*; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid / Q000627:therapeutic use*; D005990:Glycerol / Q000633:toxicity; D006242:Haptoglobins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008298:Maleates / Q000633:toxicity; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051379:Mice; D020011:Protective Agents / Q000627:therapeutic use*; D011524:Protoporphyrins / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D019209:Troponin C / Q000097:blood; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: D000510:Alpha-Globulins; D005290:Ferric Compounds; D006242:Haptoglobins; D064451:Hepcidins; C556062:IL10 protein, mouse; D008298:Maleates; D008665:Metalloporphyrins; D020011:Protective Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; D019209:Troponin C; D000515:alpha 1-Antitrypsin; C016001:alpha-1-microglobulin; D016753:Interleukin-10; D006466:Hemopexin; C030272:maleic acid; D003404:Creatinine; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D000077605:Ferric Oxide, Saccharated; D005990:Glycerol; D005937:Glucaric Acid
keywords: acute kidney injury; ischemia–reperfusion; nephrotoxicity