title: Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion.
abstract: Reactive oxygen species (ROS) contribute to the ischemia-reperfusion injury. In kidney, the intracellular sources of ROS during ischemia-reperfusion are still unclear. In the present study, we investigated the role of the catecholamine-degrading enzyme monoamine oxidases (MAOs) in hydrogen peroxide (H2O2) generation after reperfusion and their involvement in cell events leading to tissue injury and recovery. In a rat model of renal ischemia-reperfusion, we show concomitant MAO-dependent H2O2 production and lipid peroxidation in the early reperfusion period. Rat pretreatment with the irreversible MAO inhibitor pargyline resulted in the following: i) prevented H2O2 production and lipid peroxidation; ii) decreased tubular cell apoptosis and necrosis, measured by TUNEL staining and histomorphological criteria; and iii) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression. MAO inhibition also prevented Jun N-terminal kinase phosphorylation and promoted extracellular signal-regulated kinase activation, two mitogen-activated protein kinases described as a part of a "death" and "survival" pathway after ischemia-reperfusion. This work demonstrates the crucial role of MAOs in mediating the production of injurious ROS, which contribute to acute apoptotic and necrotic cell death induced by renal ischemia-reperfusion in vivo. Targeted inhibition of these oxidases could provide a new avenue for therapy to prevent renal damage and promote renal recovery after ischemia-reperfusion.
authors.affiliation: INSERM U388, IFR31, Institut Louis Bugnard, CHU Rangueil, Toulouse 31403 Cedex 4, France.
authors.forename: Oxana R
authors.initials: OR
authors.lastname: Kunduzova
authors.forename: Pascale
authors.initials: P
authors.lastname: Bianchi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pizzinat
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Escourrou
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Seguelas
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Claudie
authors.initials: C
authors.lastname: Cambon
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009336:Necrosis; D010293:Pargyline / Q000494:pharmacology; D051381:Rats; D012038:Regeneration; D015427:Reperfusion Injury / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases