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J. Biol. Chem., Vol. 278, Issue 29, 27256-27266, July 18, 2003

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Inducible Nitric-oxide Synthase Is an Important Contributor to Prolonged Protective Effects of Ischemic Preconditioning in the Mouse Kidney^*

Kwon Moo Park  , Ji-Yeon Byun  , Cornelis Kramers  , Jee In Kim  , Paul L. Huang ¶ and Joseph V. Bonventre  || ** 

From the ^||Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, the Renal Unit, Medical Services, and ^¶Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, and the ^**Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston and Cambridge, Massachusetts 02139

Ischemic preconditioning renders the mouse kidney resistant to subsequent ischemia. Understanding the mechanisms responsible for ischemic preconditioning is important for formulating therapeutic strategies aimed at mimicking protective mechanisms. We report that the resistance afforded by 30 min of bilateral kidney ischemia persists for 12 weeks after preconditioning. The protection is reflected by improved postischemic renal function, reduced leukocyte infiltration, reduced postischemic disruption of the actin cytoskeleton, and reduced postischemic expression of kidney injury molecule-1 (Kim-1). The protection is observed in both BALB/c and C57BL/6J strains of mice. Thirty minutes of prior ischemia increases the expression of inducible nitric-oxide synthase (iNOS) and endothelial NOS (eNOS) and the expression of heat shock protein (HSP)-25 and is associated with increased interstitial expression of -smooth muscle actin (-SMA), an indication of long term postischemic sequelae. Treatment with N-nitro-L-arginine (L-NNA), an inhibitor of NO synthesis, increases kidney susceptibility to ischemia. Gene deletion of iNOS increases kidney susceptibility to ischemia, whereas gene deletion of eNOS has no effect. Pharmacological inhibition of NOS by L-NNA or L-N6-(1-iminoethyl) lysine (L-NIL, a specific inhibitor of iNOS) mitigates the kidney protection afforded by 30 min of ischemic preconditioning. Fifteen minutes of prior ischemic preconditioning, which does not result in the disruption of the actin cytoskeleton, impairment of renal function, increased interstitial -SMA, or increased iNOS or eNOS expression, but does increase HSP-25 expression, partially protects the kidney from ischemia on day 8 via a mechanism that is not abolished by L-NIL treatment. Thus, iNOS is responsible for a significant component of the long term protection afforded the kidney by ischemic preconditioning, which results in persistent renal interstitial disease, but does not explain the preconditioning seen with shorter periods of ischemia.

Received for publication, February 19, 2003

^* This work was supported by the Gambro USA Young Investigator Grant of the National Kidney Foundation (to K. M. P.) and National Institutes of Health Awards DK 39773, DK 38452, and NS 10828 (to J. V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: MRB4, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. Tel.: 617-732-6020; Fax: 617-582-6010; E-mail: joseph_bonventre{at}hms.harvard.edu.

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