title: Complement activation by tubular cells is mediated by properdin binding.
abstract: Activation of filtered complement products on the brush border of the tubular epithelium is thought to be a key factor underlying proteinuria-induced tubulointerstitial injury. However, the mechanism of tubular complement activation is still unclear. Recent studies on mechanisms of complement activation indicate a key role for properdin in the initiation of an alternative pathway. We hypothesized that properdin serves as a focal point for complement activation on the tubulus. We observed a strong staining for properdin on the luminal surface of the tubules in kidney biopsies from patients with proteinuric renal disease. In vitro experiments revealed dose-dependent binding of properdin to proximal tubular epithelial cells (PTEC), whereas no significant binding to endothelial cells was detected. Exposure of PTEC with normal human serum as a source of complement resulted in complement activation with deposition of C3 and generation of C5b-9. These effects were virtually absent with properdin-deficient serum. Preincubation of PTEC with properdin before addition of properdin-depleted serum fully restored complement activation on the cells, strongly suggesting a key role for properdin in the activation of complement at the tubular surface. In proteinuric renal disease, filtered properdin may bind to PTEC and act as a focal point for alternative pathway activation. We propose that this contribution of properdin is pivotal in tubular complement activation and subsequent damage. Interference with properdin binding to tubular cells may provide an option for the treatment of proteinuric renal disease.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Gaarkeuken
authors.forename: Machiel A
authors.initials: MA
authors.lastname: Siezenga
authors.forename: Kim
authors.initials: K
authors.lastname: Zuidwijk
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Berger