title: Isothiocyanate-cysteine conjugates protect renal tissue against cisplatin-induced apoptosis via induction of heme oxygenase-1.
abstract: Heme oxygenase-1 (HO-1) is a redox sensitive inducible enzyme endowed with important antioxidant and cytoprotective activities. Here we report that two water-soluble isothiocyanate-cysteine conjugates, S-[N-benzyl(thiocarbamoyl)]-l-cysteine (BTTC) and S-[N-(3-phenylpropyl)(thiocarbamoyl)]-l-cysteine (PTTC), potently increase HO-1 protein expression and heme oxygenase activity in renal tubular epithelial cells at 5 and 10μM, while higher concentrations are themselves cytotoxic and pro-apoptotic. Inhibitors of the pro-survival pathways ERK, MAPK and PI3K almost completely abolished the increase in HO-1 induction and heme oxygenase activity, while the JNK pathway appeared to be mainly involved in the apoptosis triggered by the isothiocyanates. We also found that renal cells exposed to 50μM cisplatin (CDDP), a chemotherapeutic agent known for its nephrotoxic actions, displayed a marked increase in caspase-3 activity and the number of apoptotic cells. These effects were abolished by pre-incubation of cells with concentrations of BTCC or PTCC that maximize HO-1 induction and were reversed by the inhibitor of heme oxygenase activity tin protoporphyrin IX (SnPPIX). Moreover, in a model of CDDP-induced nephrotoxicity in vivo, pre-treatment of rats with a daily dose of BTCC or PTCC (25mg/kg, i.p.) completely abolished the increase in serum creatinine and urea levels and markedly reduced the severity of renal tissue apoptosis caused by CDDP. The renoprotective effects of BTCC and PTCC in vivo were markedly attenuated by administration of rats with SnPPIX. These findings indicate that water-soluble isothiocyanates counteract renal dysfunction and apoptosis by up-regulating the HO-1 system and could be used as a supplementary treatment to mitigate CDDP-induced nephrotoxic effects.
authors.affiliation: Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, United Kingdom.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Tayem
authors.affiliation: Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Green
authors.affiliation: Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France; Inserm U955, Equipe 3, F-94000 Créteil, France. Electronic address: roberto.motterlini@inserm.fr.
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.affiliation: Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France; Inserm U955, Equipe 3, F-94000 Créteil, France. Electronic address: roberta.foresti@inserm.fr.
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018374:LLC-PK1 Cells; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology*; D014508:Urea / Q000097:blood
chemical_list: D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C000593475:S-(N-benzyl(thiocarbamoyl))cysteine; D013859:Thiocarbamates; C072352:S-(N-(3-phenylpropyl)(thiocarbamoyl))-cysteine; D014508:Urea; D003404:Creatinine; D051547:Heme Oxygenase-1; D011494:Protein Kinases; D053148:Caspase 3; D003545:Cysteine; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Heme oxygenase-1; Nephrotoxicity; Renoprotection; Tubular epithelial cells