title: In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis.
abstract: Contrast-induced nephropathy accounts for >10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor early and late outcome. Mechanisms of contrast-induced nephropathy are not completely understood. In vitro data suggests that contrast media (CM) induces a direct toxic effect on renal tubular cells through the activation of the intrinsic apoptotic pathway. It is unclear whether this effect has a role in the clinical setting. In this work, we evaluated the effects of CM both in vivo and in vitro. By analyzing urine samples obtained from patients who experienced contrast-induced acute kidney injury (CI-AKI), we verified, by western blot and immunohistochemistry, that CM induces tubular renal cells apoptosis. Furthermore, in cultured cells, CM caused a dose-response increase in reactive oxygen species (ROS) production, which triggered Jun N-terminal kinases (JNK1/2) and p38 stress kinases marked activation and thus apoptosis. Inhibition of JNK1/2 and p38 by different approaches (i.e. pharmacological antagonists and transfection of kinase-death mutants of the upstream p38 and JNK kinases) prevented CM-induced apoptosis. Interestingly, N-acetylcysteine inhibited ROS production, and thus stress kinases and apoptosis activation. Therefore, we conclude that CM-induced tubular renal cells apoptosis represents a key mechanism of CI-AKI.
authors.affiliation: Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Quintavalle
authors.forename: M
authors.initials: M
authors.lastname: Brenca
authors.forename: F
authors.initials: F
authors.lastname: De Micco
authors.forename: D
authors.initials: D
authors.lastname: Fiore
authors.forename: S
authors.initials: S
authors.lastname: Romano
authors.forename: M F
authors.initials: MF
authors.lastname: Romano
authors.forename: F
authors.initials: F
authors.lastname: Apone
authors.forename: A
authors.initials: A
authors.lastname: Bianco
authors.forename: M A
authors.initials: MA
authors.lastname: Zabatta
authors.forename: G
authors.initials: G
authors.lastname: Troncone
authors.forename: C
authors.initials: C
authors.lastname: Briguori
authors.forename: G
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003287:Contrast Media / Q000009:adverse effects*; D057075:Enzyme Assays; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; D003287:Contrast Media; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3