Received for publication January 2, 2003.
Revised January 24, 2003.
Accepted for publication April 3, 2003.

Nitric Oxide Inhibitor L-NAME Potentiates Induction of Heme Oxygenase-1 in Kidney Ischemia/Reperfused Model; a novel mechanism for regulation of the oxygenase

Abstract

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, while 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 NOS activity by L-NAME at 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, PBN, in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. 24h 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 4h in the presence or absence of 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 1h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; and 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.

Key words: bile pigments, carbon monoxide, heme oxygenase isozymes, ischemic kidney, nitric oxide radicals, oxidative stress

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