Provinol Prevents CsA-induced Nephrotoxicity by Reducing Reactive Oxygen Species, iNOS and NF-kB Expression

B. Buffoli ¹, O. Pechánová ¹, S. Kojová ¹, R. Andriantsitohaina ¹, L. Giugno ¹, R. Bianchi ¹ and R. Rezzani ^1*

¹ Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (BB,LG,RB,RR); Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic (OP,SK); and Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, Illkirch, France (RA)

^* To whom correspondence should be addressed. E-mail: rezzani{at}med.unibs.it.

Submitted on January 14, 2005
Accepted on 4 May 2005

	Abstract

The Cyclosporine A (CsA) use is associated with several side effects, the most important of which is nephrotoxicity that includes, as we previously showed, tubular injury and interstitial fibrosis. Recently, the interest of many researchers has been pointed to minimize these effects by pharmacological interventions. For this aim we tested whether the administration of a red wine polyphenol, Provinol (PV), prevents the development of CsA-induced nephrotoxicity. Rats were treated for 21 days and divided into four groups: control; group treated with PV (40 mg/kg/day, by oral administration in tap water); group treated with CsA (15 mg/kg/day, by subcutaneous injection); group treated with CsA plus PV. CsA produced a significant increase of systolic blood pressure, did not affect urinary output but caused a significant decrease in creatinine clearance. These side effects were associated with an increase in conjugated dienes, which are lipid peroxidation products, inducible NO-synthase (iNOS) and nuclear factor NF-kB, which are involved in antioxidant damage. However, PV prevented these negative effects through a protective mechanism that involved reduction of both oxidative stress and increased iNOS and NF-kB expression induced by CsA. These results provide a pharmacological basis for the beneficial effects of plant-derived polyphenols against CsA-induced renal damage associated with CsA.

Key Words: fibrosis, kidney, provinol, ROS

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