In vivo inhibition of renal heme oxygenase with an imidazole-dioxolane inhibitor

Recent studies have identified imidazole-dioxolane based compounds as novel heme oxygenase (HO) 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). After 5 days, QC-13 was delivered either by continuous intrarenal medullary interstitial infusion (IRMI) into one kidney at several concentrations for 72 h or by two intraperitoneal injections over a 48-h period. IRMI infusion of QC-13 at a concentration of 25 microM resulted in a significant decrease in medullary but not cortical HO activity as compared to CoPP treated kidneys. IRMI infusion of QC-13 at a lower concentration (2.5 microM) had no effect on either medullary or cortical HO activity in CoPP treated mice. In contrast, administration of QC-13 at a higher concentration (250 microM) resulted in a significant decrease in both medullary and cortical HO activity in CoPP treated mice. Systemic administration of QC-13 resulted in significant decrease both renal cortical and medullary HO activity in CoPP treated mice. 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 renal HO inhibitors in vivo and can inhibit HO 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.