title: Upregulation of nuclear factor-κB activity mediates CYP24 expression and reactive oxygen species production in indoxyl sulfate-induced chronic kidney disease.
abstract: OBJECTIVE
  Chronic kidney disease (CKD) is associated with an inflammation-mediated process, and the vitamin D (3) catabolizing enzyme, CYP24, is frequently overexpressed in CKD, where it may play a crucial role in kidney disease.
  
  
  METHODS
  Herein, in this study, we investigated CYP24, reactive oxygen species (ROS), and inflammatory responses in an indoxyl sulfate (IS)-induced CKD model to elucidate the role of CYP24 in CKD.
  
  
  RESULTS
  Our results showed that IS upregulates proinflammatory cytokine, CYP24 and nuclear factor-κB (NF-κB) expression in human renal proximal tubule epithelial cells. In addition, IS treatment increased ROS production and simultaneously upregulated CYP24 expression and NF-κB translocation. Moreover, the IS-induced upregulation of CYP24 expression was alleviated by an inhibitor of NF-κB, as well as a siRNA specific to NF-κB p65. Furthermore, the renal cortex of DN (Dahl salt-resistant normotensive) + IS, DH (Dahl salt-sensitive hypertensive), and DH + IS rats showed increased expression of NF-κB p65, CYP24, 8-hydroxydeoxyguanosine (8-OHdG), a marker of ROS and macrophage infiltration compared with DN rats.
  
  
  CONCLUSIONS
  These results provide evidence that administration of IS in human renal tubular epithelial cells upregulates NF-κB, which leads to increase CYP24 expression and ROS production. They also suggest that suppressing NF-κB signalling is promising for the development into a strategy for CKD treatment.
authors.affiliation: Division of Blood Purification, The Second Hospital of Hebei Medical University, No. 215 Peace Road, Shijiazhuang, 053000, Hebei, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Blood Purification, The Second Hospital of Hebei Medical University, No. 215 Peace Road, Shijiazhuang, 053000, Hebei, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Division of Blood Purification, The Second Hospital of Hebei Medical University, No. 215 Peace Road, Shijiazhuang, 053000, Hebei, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Blood Purification, The Second Hospital of Hebei Medical University, No. 215 Peace Road, Shijiazhuang, 053000, Hebei, China.
authors.forename: Yongning
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D045744:Cell Line, Tumor; D000072498:Cytochrome P450 Family 24 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006973:Hypertension / Q000150:complications; D007200:Indican / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C498143:RELA protein, human; D017382:Reactive Oxygen Species; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000072498:Cytochrome P450 Family 24; D003849:Deoxyguanosine; D007200:Indican
keywords: CYP24; chronic kidney disease; cytokine; nuclear factor-κB