Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule.
Nephrotoxicity is one of the main side effects caused by cisplatin (CP), a widely used antineoplastic 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-PK(1) cells to CP (50 microM) caused significant apoptosis as evidenced by caspase-3 activation and an increased number of floating cells. Treatment with CORM-3 (1-50 microM) 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 1H-oxadiazole [4, 3-a] quinoxaline-1-ore (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 corticomedullary junction. A daily administration of CORM-3 (10 mg/kg ip), starting 1 day before 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, a decreased number of apoptotic tubular cells, and an 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 an effective therapeutic adjuvant in the treatment of CP-induced nephrotoxicity.
Tayem
Yasin
Y
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK.
Johnson
Tony R
TR
Mann
Brian E
BE
Green
Colin J
CJ
Motterlini
Roberto
R
D000818:Animals; D002248:Carbon Monoxide / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018374:LLC-PK1 Cells; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000517:prevention & control*; D013552:Swine
D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D006152:Cyclic GMP; D002945:Cisplatin