title: Binding of factor H to tubular epithelial cells limits interstitial complement activation in ischemic injury.
abstract: Factor H is a regulator of the alternative pathway of complement, and genetic studies have shown that patients with mutations in factor H are at increased risk for several types of renal disease. Pathogenic activation of the alternative pathway in acquired diseases, such as ischemic acute kidney injury, suggests that native factor H has a limited capacity to control the alternative pathway in the kidney. Here we found that an absolute deficiency of factor H produced by gene deletion prevented complement activation on tubulointerstitial cells after ischemia/reperfusion (I/R) injury, likely because alternative pathway proteins were consumed in the fluid phase. In contrast, when fluid-phase regulation by factor H was maintained while the interaction of factor H with cell surfaces was blocked by a recombinant inhibitor protein, complement activation after renal I/R increased. Finally, a recombinant form of factor H, specifically targeted to sites of C3 deposition, reduced complement activation in the tubulointerstitium after ischemic injury. Thus, although factor H does not fully prevent activation of the alternative pathway of complement on ischemic tubules, its interaction with the tubule epithelial cell surface is critical for limiting complement activation and attenuating renal injury after ischemia.
authors.affiliation: Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Renner
authors.forename: Viviana P
authors.initials: VP
authors.lastname: Ferreira
authors.forename: Claudio
authors.initials: C
authors.lastname: Cortes
authors.forename: Ryan
authors.initials: R
authors.lastname: Goldberg
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pangburn
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Amanda
authors.initials: A
authors.lastname: Holland-Neidermyer
authors.forename: Derek
authors.initials: D
authors.lastname: Strassheim
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
mesh_terms: D000818:Animals; D003167:Complement Activation; D017242:Complement Factor H / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D004847:Epithelial Cells / Q000378:metabolism*; D045604:Extracellular Fluid / Q000276:immunology; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D011485:Protein Binding; D015427:Reperfusion Injury / Q000276:immunology*
chemical_list: D017242:Complement Factor H