title: Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy.
abstract: BACKGROUND
  We have previously documented that human mesangial cell (HMC)-derived tumour necrosis factor-alpha (TNF-alpha) is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the function of podocytes in IgAN.
  
  
  METHODS
  Podocyte markers were examined in renal tissues by immunofluorescence. In vitro experiments were conducted with podocytes cultured with polymeric IgA (pIgA) or conditioned medium prepared from HMC incubated with pIgA (IgA-HMC conditioned medium).
  
  
  RESULTS
  Glomerular immunostaining for nephrin or ezrin was significantly weaker in patients with IgAN. The immunostaining of IgA and nephrin was distinctly separate with no co-localization. In vitro experiments revealed no effect of pIgA on the expression of these podocyte proteins as IgA from IgAN patients did not bind to podocytes. In contrast, IgA conditioned medium prepared from IgAN patients down-regulated the expression of these podocyte proteins as well as other podocyte markers (podocin and synaptopodin) in cultured podocytes. The mRNA expression of nephrin, erzin, podocin but not synaptopodin correlated with the degree of proteinuria and creatinine clearance. The down-regulation was reproducible in podocytes cultured with TNF-alpha or transforming growth factor-beta (TGF-beta) at concentration comparable to that in the IgA-HMC conditioned medium. The expression of these podocyte proteins was restored partially with a neutralizing antibody against TNF-alpha or TGF-beta and fully with combination of both antibodies.
  
  
  CONCLUSIONS
  Our finding suggests podocyte markers are reduced in IgAN. An in vitro study implicates that humoral factors (predominantly TNF-alpha and TGF-beta) released from mesangial cells are likely to alter the glomerular permeability in the event of proteinuria and tubulointerstitial injury in IgAN.
authors.affiliation: Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. knlai@hkucc.hku.hk
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Ka Ying
authors.initials: KY
authors.lastname: Tam
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.forename: Fernand M
authors.initials: FM
authors.lastname: Lai
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002470:Cell Survival; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D050527:Mesangial Cells / Q000276:immunology*; D015676:Osteonectin / Q000235:genetics; D050199:Podocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099149:Ezrin
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D016207:Cytokines; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D007070:Immunoglobulin A; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D015676:Osteonectin; D012333:RNA, Messenger; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D014409:Tumor Necrosis Factor-alpha; D000099149:Ezrin; C113267:nephrin; C516888:PTPRO protein, human