title: Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity.
abstract: Hypoxia-inducible factor (HIF)-1 is a transcription factor mediating cellular response to hypoxia. Although it is expressed in tubular cells of the ischemic kidney, its functional role is not fully clarified in the pathological context. In this study, we investigated a role of HIF in tubular cell apoptosis induced by cisplatin. HIF-1alpha was expressed in tubular cells in the outer medulla 3 days after cisplatin (6 mg/kg) administration. With the in vivo administration of cobalt to activate HIF, the number of apoptotic renal tubular cells became much smaller in the outer medulla, compared with the vehicle group. We also examined the functional role of HIF-1 in vitro using immortalized rat proximal tubular cells (IRPTC). In hypoxia, IRPTC that express dominant-negative (dn) HIF-1alpha showed impaired survival in cisplatin injury at variable doses (25-100 microM, 24 h), which was not obvious in normoxia. The observed difference in cell viability in hypoxia was associated with the increased number of apoptotic cells in dnHIF-1alpha clones (Hoechst 33258 staining). Studies on intracellular signaling revealed that the degree of cytochrome c release, dissipation of mitochondrial membrane potentials, and caspase-9 activity were all more prominent in dnHIF-1alpha clones than in control IRPTC, pointing to the accelerated signaling of mitochondrial pathways. We propose that HIF-1 mediates cytoprotection against cisplatin injury in hypoxic renal tubular cells, by reducing the number of apoptotic cells through stabilization of mitochondrial membrane integrity and suppression of apoptosis signaling. A possibility was suggested that activation of HIF-1 could be a new promising therapeutic target for hypoxic renal diseases.
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kojima
authors.forename: Takamoto
authors.initials: T
authors.lastname: Ohse
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival; D002945:Cisplatin / Q000009:adverse effects*; D045304:Cytochromes c / Q000378:metabolism; D020869:Gene Expression Profiling; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D008564:Membrane Potentials; D016133:Polymerase Chain Reaction; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D045304:Cytochromes c; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin