Premium
In vivo Inhibition of Renal Heme Oxygenase‐1 with an Imidazole‐Dioxolane Inhibitor, QC‐13.
Author(s) -
Csongradi Eva,
Vera Trinity,
Stec David E.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1025.4
Subject(s) - copp , in vivo , chemistry , medulla , pharmacology , heme oxygenase , kidney , endocrinology , biochemistry , heme , medicine , biology , enzyme , microbiology and biotechnology
Recent studies have indentified imidazole‐dioxolane based compounds as novel heme oxyenase inhibitors. While these compounds have been demonstrated to be specific HO inhibitors in vitro, they have yet to be used to inhibit renal HO activity in vivo. The goal of this study was to determine the effectiveness of the imidazole‐dioxolane HO‐1 inhibitor, QC‐13, in the inhibition of renal HO activity in vivo. HO‐1 was induced in mice by treatment with cobalt protoporphyrin (COPP, 50 mg/kg, sc.). After 5 days, QC‐13 was delivered either by continuous intrarenal medullay interstitial (IRMI) infusion (25 μM) for 72 hours or by two i.p injections (52 mg/kg) over a 48 hour period. IRMI infusion of QC‐13 resulted in a 46 ± 14 % decrease in medullary HO activity as compared to control CoPP treated medulla (n=5). IRMI infusion of QC‐13 had no significant effect on cortical HO activity which averaged 107 ± 17 % of COPP treated cortex (n=5). In contrast, the systemic administration of QC‐13 resulted in significant decrease in renal cortical HO activity but had no significant effect on medullary HO activity with HO activity averaging 48 ± 8 %, and 79 ± 12 % of control CoPP treated mice in cortex and medulla, respectively. In contrast to classical porphyrin based HO inhibitors, IRMI infusion of QC‐13 did not induce HO‐1 protein levels as determined by Western blot analysis of medullary protein samples. Our results demonstrated that imidazole‐dioxolane inhibitors are selective HO‐1 inhibitors in vivo which can inhibit HO‐1 activity independent of HO‐1 induction. These inhibitors may be useful tools to elucidate the role of renal HO‐1 in numerous physiologic and pathophysiologic conditions. This study was supported by NIH grants HL‐088421 and HL‐088421‐S1.