title: Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage.
abstract: BACKGROUND
  Urinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH).
  
  
  METHODS
  In the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay.
  
  
  RESULTS
  The U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes.
  
  
  CONCLUSIONS
  In the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nagamachi
authors.forename: Isao
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Hiyori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoshita
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hisada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Honda
authors.forename: Mamiko
authors.initials: M
authors.lastname: Shimamoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Horikoshi
authors.affiliation: Division of Nephrology, Department of Internadl Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan. yasu@juntendo.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D000328:Adult; D003167:Complement Activation; D017242:Complement Factor H / Q000652:urine*; D015938:Complement Membrane Attack Complex / Q000652:urine*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007674:Kidney Diseases / Q000473:pathology / Q000652:urine*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011414:Properdin / Q000652:urine*
chemical_list: D015938:Complement Membrane Attack Complex; D011414:Properdin; D017242:Complement Factor H