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. 2013 Feb;56(1):6-14.
doi: 10.1503/cjs.004811.

Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury

Asli Korkmaz  1 , Dürdane Kolankaya
Affiliations

Inhibiting inducible nitric oxide synthase with rutin reduces renal ischemia/reperfusion injury

Asli Korkmaz et al. Can J Surg. 2013 Feb.

Abstract
in English, French

Background: Nitric oxide (NO) seems to play an important role during renal ischemia/reperfusion (I/R) injury. We investigated whether rutin inhibits inducible nitric oxide synthase (iNOS) and reduces 3-nitrotyrosine (3-NT) formation in the kidneys of rats during I/R.

Methods: Wistar albino rats were nephrectomized unilaterally and, 2 weeks later, subjected to 45 minutes of left renal pedicle occlusion followed by 3 hours of reperfusion. We intraperitoneally administered L-N6-(1-iminoethyl)lysine (L-NIL; 3 mg/kg) for 30 minutes or rutin (1 g/kg) for 60 minutes before I/R. After reperfusion, kidney samples were taken for immunohistochemical analysis of iNOS and 3-NT. We measured plasma nitrite/nitrate and cyclic guanosine monophosphate (cGMP) to evaluate NO levels.

Results: Ischemia/reperfusion caused plasma cGMP to increase significantly. Similarly, plasma nitrite/nitrate was elevated in the I/R group compared with the control group. Histochemical staining was positive for iNOS and 3-NT in the I/R group. Pretreatment with L-NIL or rutin significantly mitigated the elevation of plasma cGMP and nitrite/nitrate. These changes in biochemical parameters were also associated with changes in immunohistochemical appearance. Pretreatment with L-NIL or rutin significantly decreased the incidence and severity of iNOS and 3-NT formation in the kidney tissues.

Conclusion: Our findings suggest that high activity of iNOS causes renal I/R injury, and that rutin exerts protective effects, probably by inhibiting iNOS.

Contexte: L’oxyde nitrique (NO) semble jouer un rôle important durant la lésion d’ischémie/reperfusion (I/R) rénale. Nous avons vérifié si la rutine inhibe l’oxyde nitrique synthase inductible (iNOS) et réduit la formation de 3-nitrotyrosine (3-NT) dans les reins de rats durant l’I/R.

Méthodes: Des rats albinos Wistar ont subi une néphrectomie unilatérale avant d’être soumis 2 semaines plus tard à une occlusion du pédicule rénal gauche d’une durée de 45 minutes, suivie de 3 heures de reperfusion. Nous avons administré de la L-N6-(1-iminoéthyl)lysine (L-NIL; 3 mg/kg) par voie intrapéritonéale pendant 30 minutes ou de la rutine (1 g/kg) pendant 60 minutes avant l’I/R. Après la reperfusion, des échantillons de tissu rénal ont été prélevés pour analyse immunohistochimique de l’iNOS et de la 3-NT. Nous avons mesuré les taux plasmatiques de nitrite/nitrate et de guanosine monophosphate cyclique (cGMP) pour évaluer les taux de NO.

Résultats: L’ischémie/reperfusion a causé une augmentation significative du cGMP plasmatique. De même, les taux de nitrite/nitrate plasmatiques ont augmenté dans le groupe soumis à l’I/R, comparativement au groupe témoin. Les épreuves de coloration histochimique ont donné des résultats positifs pour l’iNOS et la 3-NT dans le groupe soumis à l’I/R. Un prétraitement par L-NIL ou rutine a significativement atténué l’élévation des taux de cGMP plasmatique et de nitrite/nitrate. Ces changements des paramètres biochimiques ont aussi été associés à des changements de l’aspect immunohistochimique. Le prétraitement au moyen de L-NIL ou de rutine a significativement réduit l’incidence et l’ampleur de la formation d’iNOS et de 3-NT dans les tissus rénaux.

Conclusion: Nos observations donnent à penser qu’une forte activité de l’iNOS provoque la lésion I/R rénale et que la rutine confère une protection, probablement en inhibant l’iNOS.

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Figures

Fig. 1
Fig. 1
Immunohistochemical evidence of expression of inducible nitric oxide synthase in the cortex of a rat kidney following ischemia/reperfusion (I/R). Panels refer to the following treatment groups: (A) negative control without primary antibody, (B) sham, (C) right nephrectomy control, (D) right nephrectomy + I/R, (E) right nephrectomy + L-N6-(1-iminoethyl)lysine + I/R, and (F) right nephrectomy + rutin + I/R. Magnification ×400.
Fig. 2
Fig. 2
Immunohistochemical evidence of 3-nitrotyrosine formation in the cortex of a rat kidney following ischemia/reperfusion (I/R). Panels refer to the following treatment groups: (A) negative control without primary antibody, (B) sham, (C) right nephrectomy control, (D) right nephrectomy + I/R, (E) right nephrectomy + L-N6-(1-iminoethyl)lysine + I/R, and (F) right nephrectomy + rutin + I/R. Magnification ×400.
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