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

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 α-smooth muscle actin (α-SMA), an indication of long term postischemic sequelae. Treatment with Nω-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 LNNA 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 α-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... [ABSTRACT FROM AUTHOR]