TY - JOUR T1 - Nitric Oxide Inhibitor <em>N</em><sup>ω</sup>-Nitro-<span class="sc">l</span>-arginine Methyl Ester Potentiates Induction of Heme Oxygenase-1 in Kidney Ischemia/Reperfusion Model: A Novel Mechanism for Regulation of the Oxygenase JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 43 LP - 50 DO - 10.1124/jpet.102.048686 VL - 306 IS - 1 AU - Robert D. Mayer AU - Xiaojun Wang AU - Mahin D. Maines Y1 - 2003/07/01 UR - http://jpet.aspetjournals.org/content/306/1/43.abstract N2 - The biological significance of the heme oxygenase (HO) system's response to stress reflects functions of its products—CO and bile pigments. CO is a messenger molecule, whereas bile pigments are antioxidants and modulators of cell signaling. Presently, an unexpected mechanism for sustained suprainduction of renal HO-1 following ischemia/reperfusion injury is described. Inhibition of nitric-oxide synthase (NOS) activity by Nω-nitro-l-arginine methyl ester (l-NAME) at the resumption of reperfusion of rat kidney subjected to bilateral ischemia (30 min) was as effective as the most potent HO-1 inducer, the spin trap agent n-tert-butyl-α-phenyl nitrone (PBN), in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. Twenty-four hours after reperfusion, HO-1 mRNA measured ∼30-fold that of the control in the presence of l-NAME treatment; in its absence, the transcript increased to only ∼5-fold. At 4 h in the presence or absence of the l-NAME HO-1, mRNA was increased by ∼30-fold. The transcript was translated to active protein as indicated by Western blotting, immunohistochemistry, and activity analyses. l-NAME was not effective given 1 h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; ferritin expression in the kidney was not effected. It is reasoned that in tissue directly insulted by ischemia/reperfusion, increased production of NO radicals promotes the loss of HO-1 transcript. Because the absence of NO radicals and presence of PBN had a similar effect on HO-1, we propose that suprainduction of the gene is mainly caused by O2 radicals formed on reperfusion. Inhibition of NOS is potentially useful for sustained induction of HO-1 in organs that will be subjected to oxidative-stress insult. The American Society for Pharmacology and Experimental Therapeutics ER -