title: Differential effects of caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney.
abstract: Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia-reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure.
authors.affiliation: Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Queen Mary, University of London, UK. p.k.chatterjee@brighton.ac.uk
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Chatterjee
authors.forename: Zoran
authors.initials: Z
authors.lastname: Todorovic
authors.forename: Ahila
authors.initials: A
authors.lastname: Sivarajah
authors.forename: Helder
authors.initials: H
authors.lastname: Mota-Filipe
authors.forename: Paul A J
authors.initials: PA
authors.lastname: Brown
authors.forename: Keith N
authors.initials: KN
authors.lastname: Stewart
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D015415:Biomarkers; D053148:Caspase 3; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D015843:Serpins / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014764:Viral Proteins / Q000494:pharmacology
chemical_list: D001593:Benzyl Compounds; D015415:Biomarkers; C476029:Boc-D-FMK; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006845:Hydrocarbons, Fluorinated; D009842:Oligopeptides; D015843:Serpins; D014764:Viral Proteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; C074641:interleukin-1beta-converting enzyme inhibitor; D009195:Peroxidase; C505410:Casp3 protein, rat; D053148:Caspase 3