title: Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury.
abstract: Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Laskowski
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Renner
authors.affiliation: Department of Nephrology and Renal Transplantation, Lapeyronnie Hospital, Montpellier, France.
authors.forename: Moglie
authors.initials: M
authors.lastname: Le Quintrec
authors.affiliation: Department of Medicine, University of Wisconsin Madison, Madison, WI, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Panzer
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Hannan
authors.affiliation: Department of Pathology, University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, UK.
authors.forename: Marieta M
authors.initials: MM
authors.lastname: Ruseva
authors.affiliation: Department of Microbiology and Immunology, Meharry Medical College, Nashville, TN, USA.
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Antonioli
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address: Joshua.Thurman@ucdenver.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D017463:Receptors, Complement 3b
chemical_list: D003176:Complement C3; C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017242:Complement Factor H
keywords: complement; glomerulonephritis; inflammation