title: c-mip down-regulates NF-κB activity and promotes apoptosis in podocytes.
abstract: The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-κB may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-κB has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-κB family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of RelA prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a close spatial relationship. These results suggest that alterations in NF-κB activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS.
authors.affiliation: INSERM, U955, Créteil, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Ory
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Fan
authors.forename: Nabila
authors.initials: N
authors.lastname: Hamdaoui
authors.forename: Shao-yu
authors.initials: SY
authors.lastname: Zhang
authors.forename: Dominique
authors.initials: D
authors.lastname: Desvaux
authors.forename: Vincent
authors.initials: V
authors.lastname: Audard
authors.forename: Marina
authors.initials: M
authors.lastname: Candelier
authors.forename: Laure-Helene
authors.initials: LH
authors.lastname: Noel
authors.forename: Philippe
authors.initials: P
authors.lastname: Lang
authors.forename: Georges
authors.initials: G
authors.lastname: Guellaën
authors.forename: Andre
authors.initials: A
authors.lastname: Pawlak
authors.forename: Djillali
authors.initials: D
authors.lastname: Sahali
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000378:metabolism* / Q000473:pathology; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C540426:CMIP protein, human; D002352:Carrier Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D053148:Caspase 3