title: p38 MAPK mediates renal tubular cell TNF-alpha production and TNF-alpha-dependent apoptosis during simulated ischemia.
abstract: Ischemia causes renal tubular cell loss through apoptosis; however, the mechanisms of this process remain unclear. Using the renal tubular epithelial cell line LLC-PK(1), we developed a model of simulated ischemia (SI) to investigate the role of p38 MAPK (mitogen-activated protein kinase) in renal cell tumor necrosis factor-alpha (TNF-alpha) mRNA production, protein bioactivity, and apoptosis. Results demonstrate that 60 min of SI induced maximal TNF-alpha mRNA production and bioactivity. Furthermore, 60 min of ischemia induced renal tubular cell apoptosis at all substrate replacement time points examined, with peak apoptotic cell death occurring after either 24 or 48 h. p38 MAPK inhibition abolished TNF-alpha mRNA production and TNF-alpha bioactivity, and both p38 MAPK inhibition and TNF-alpha neutralization (anti-porcine TNF-alpha antibody) prevented apoptosis after 60 min of SI. These results constitute the initial demonstration that 1) renal tubular cells produce TNF-alpha mRNA and biologically active TNF-alpha and undergo apoptosis in response to SI, and 2) p38 MAPK mediates renal tubular cell TNF-alpha production and TNF-alpha-dependent apoptosis after SI.
authors.affiliation: Department of Urology, Indiana University Medical Center, Indianapolis, Indiana 46202, USA. kkmeldrum@earthlink.net
authors.forename: K K
authors.initials: KK
authors.lastname: Meldrum
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: K L
authors.initials: KL
authors.lastname: Hile
authors.forename: E B
authors.initials: EB
authors.lastname: Yerkes
authors.forename: A
authors.initials: A
authors.lastname: Ayala
authors.forename: M P
authors.initials: MP
authors.lastname: Cain
authors.forename: R C
authors.initials: RC
authors.lastname: Rink
authors.forename: A J
authors.initials: AJ
authors.lastname: Casale
authors.forename: M A
authors.initials: MA
authors.lastname: Kaefer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004789:Enzyme Activation; D007511:Ischemia / Q000503:physiopathology*; D007684:Kidney Tubules / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D018374:LLC-PK1 Cells; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases