title: Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate.
abstract: During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (K(D) values of 32 and 93 nm, respectively). Using a library of HS-like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement-derived tubular injury in proteinuric renal diseases.
authors: Department of Nephrology, University Medical Center, 9713 GZ Groningen, The Netherlands. a.zaferani@umcg.nl
authors: Azadeh
authors: A
authors: Zaferani
authors: Romain R
authors: RR
authors: Vivès
authors: Pieter
authors: P
authors: van der Pol
authors: Gerjan J
authors: GJ
authors: Navis
authors: Mohamed R
authors: MR
authors: Daha
authors: Cees
authors: C
authors: van Kooten
authors: Hugues
authors: H
authors: Lortat-Jacob
authors: Marc A
authors: MA
authors: Seelen
authors: Jacob
authors: J
authors: van den Born
mesh_terms: D000818:Animals; D002460:Cell Line; D017242:Complement Factor H / Q000378:metabolism*; D000939:Epitopes / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011414:Properdin / Q000378:metabolism*; D011485:Protein Binding; D011507:Proteinuria / Q000378:metabolism* / Q000401:mortality; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017242:Complement Factor H; D000939:Epitopes; D006497:Heparan Sulfate; D011414:Properdin