title: Vitamin D receptor activators upregulate and rescue podocalyxin expression in high glucose-treated human podocytes.
abstract: BACKGROUND
  Vitamin D is beneficial in human and experimental chronic kidney disease, the leading cause of which is diabetic nephropathy. Vitamin D through its receptor, VDR, provides renal protection in diabetic nephropathy, but limited data exist about its effect on podocytes. Renal podocytes form the main filtration barrier possessing a unique phenotype maintained by proteins including podocalyxin and nephrin, the expression of which is suppressed in pathological conditions.
  
  
  METHODS
  We used immortalized human podocytes (human glomerular epithelial cells, HGEC) to assess podocalyxin and nephrin expression after treatment with 1,25-dihydroxyvitamin D3 (calcitriol) and its analogue paricalcitol. The involvement of VDR was investigated by silencing with hVDR-siRNA and ChIP analysis.
  
  
  RESULTS
  HGEC exhibit high glucose-mediated downregulation of podocalyxin and nephrin, loss of which has been linked with loss of the permselective renal barrier and proteinuria. Calcitriol and paricalcitol reversed high glucose-induced decrease of nephrin and significantly enhanced podocalyxin expression in podocytes cultured in high glucose. HGEC express VDR and retinoid X receptor (RXR). In the presence of calcitriol and paricalcitol, VDR expression was upregulated and VDR colocalized with RXR in the nucleus. VDR knockdown abolished the protective action of calcitriol and paricalcitol on podocalyxin expression indicating that podocalyxin activation of expression is partly mediated by VDR. Furthermore, VDR specifically regulates podocalyxin expression by bounding to a site upstream of the podocalyxin promoter.
  
  
  CONCLUSIONS
  Vitamin D analogues maintain and, furthermore, re-activate the expression of specialized components of podocytes including podocalyxin, hence they provide protection against loss of the permselective renal barrier, with molecular mechanisms elucidated herein.
authors.affiliation: Faculty of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis, Athens, Greece.
authors.forename: S N
authors.initials: SN
authors.lastname: Verouti
authors.forename: E C
authors.initials: EC
authors.lastname: Tsilibary
authors.forename: E
authors.initials: E
authors.lastname: Fragopoulou
authors.forename: C
authors.initials: C
authors.lastname: Iatrou
authors.forename: C A
authors.initials: CA
authors.lastname: Demopoulos
authors.forename: A S
authors.initials: AS
authors.lastname: Charonis
authors.forename: S A
authors.initials: SA
authors.lastname: Charonis
authors.forename: G I
authors.initials: GI
authors.lastname: Drossopoulou
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001665:Binding Sites / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D004872:Ergocalciferols / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004872:Ergocalciferols; D008565:Membrane Proteins; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D012795:Sialoglycoproteins; C113267:nephrin; C001643:podocalyxin; C084656:paricalcitol; D002117:Calcitriol; D005947:Glucose