title: NFκBiz protein downregulation in acute kidney injury: Modulation of inflammation and survival in tubular cells.
abstract: Acute kidney injury is characterized by decreased renal function, tubular cell death and interstitial inflammation. The transcription factor NF-κB is a key regulator of genes involved in cell survival and the inflammatory response. In order to better understand the regulation and role of NF-κB in acute kidney injury we explored the expression of NF-κB-related genes in experimental acute kidney injury induced by a folic acid overdose. NFκBiz, a member of the IκB family of NF-κB regulators encoding NFκBiz, was among the top up-regulated NF-κB-related genes at the mRNA level in experimental acute kidney injury. However, the NFκBiz protein was constitutively expressed by normal tubular cells but was down-regulated in experimental acute kidney injury. Kidney NFκBiz mRNA upregulation and protein downregulation was also observed in acute kidney injury induced by cisplatin or unilateral kidney injury resulting from ureteral obstruction. Thus, we studied the consequences of NFκBiz protein downregulation by specific siRNA in cultured tubular epithelial cells. NFκBiz mRNA and protein were up-regulated by inflammatory cytokines (IL-1β or TWEAK/TNFα/IFNγ) and by LPS in cultured tubular cells. However, TWEAK only induced a very mild and short lived NFκBiz upregulation. NFκBiz targeting increased chemokine production and dampened Klotho downregulation induced by TWEAK, without modulating cell proliferation. NFκBiz targeting also rendered cells more resistant to apoptosis induced by serum deprivation or inflammatory cytokines. In conclusion, NFκBiz differentially regulates NF-κB-mediated responses of tubular cells to inflammatory cytokines in a gene-specific manner, and may be of potential therapeutic interest to limit inflammation in kidney disease.
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain. Electronic address: jonay.poveda@gmail.com.
authors.forename: Jonay
authors.initials: J
authors.lastname: Poveda
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain. Electronic address: aortiz@fjd.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; Fundación Renal Iñigo Álvarez de Toledo-IRSIN and REDINREN, Madrid, Spain. Electronic address: mdsanchez@fjd.es.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D002945:Cisplatin
keywords: Acute kidney injury; Apoptosis; Inflammation; NF-κB; TNF; Transcription factor; Tweak