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1 Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom
2 Department of Chemistry, University of Sheffield, Sheffield, United Kingdom
* To whom correspondence should be addressed. E-mail: r.motterlini{at}imperial.ac.uk.
Nephrotoxicity is one of the main side effects caused by cisplatin (CP), a widely used anti-neoplastic agent. Here, we examined the effect of a novel water-soluble carbon monoxide-releasing molecule (CORM-3) on CP-mediated cytotoxicity in renal epithelial cells and explored the potential therapeutic benefits of carbon monoxide in CP-induced nephrotoxicity in vivo. Exposure of LLC-PK1 cells to CP (50 µM) caused significant apoptosis as evidenced by caspase-3 activation and increased number of floating cells. Treatment with CORM-3 (1-50 µM) resulted in a remarkable and concentration-dependent decrease in CP-induced caspase-3 activity and cell detachment. This effect involved activation of the cGMP pathway as ODQ, a guanylate cyclase inhibitor, completely abolished the protection elicited by CORM-3. Using a rat model of CP-induced renal failure, we found that treatment with CP (7.5 mg/kg) caused a significant elevation in plasma urea (6.6-fold) and creatinine (3.1-fold) levels, which was accompanied by severe morphological changes and marked apoptosis in tubules at the cortico-medullary junction. A daily administration of CORM-3 (10 mg/kg i.p.), starting 1 day prior to CP treatment and continuing for 3 days thereafter, resulted in amelioration of renal function as shown by reduction of urea and creatinine levels to basal values, decreased number of apoptotic tubular cells and improved histological profile. A negative control (iCORM-3) that is incapable of liberating CO failed to prevent renal dysfunction mediated by CP indicating that CO is directly involved in renoprotection. Our data demonstrate that CORM-3 can be used as a very effective therapeutic adjuvant in the treatment of CP-induced nephrotoxicity.
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