title: Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice.
abstract: Complement factor H (CFH) is an important regulatory protein in the alternative pathway of the complement system, and CFH polymorphisms increase the genetic risk of age-related macular degeneration dramatically. These same human CFH variants have also been associated with dense deposit disease. To mechanistically study the function of CFH in the pathogenesis of these diseases, we created transgenic mouse lines using human CFH bacterial artificial chromosomes expressing full-length human CFH variants and crossed these to Cfh knockout (Cfh(-/-)) mice. Human CFH protein inhibited cleavage of mouse complement component 3 and factor B in plasma and in retinal pigment epithelium/choroid/sclera, establishing that human CFH regulates activation of the mouse alternative pathway. One of the mouse lines, which express relatively higher levels of CFH, demonstrated functional and structural protection of the retina owing to the Cfh deletion. Impaired visual function, detected as a deficit in the scotopic electroretinographic response, was improved in this transgenic mouse line compared with Cfh(-/-) mice, and transgenics had a thicker outer nuclear layer and less sub-retinal pigment epithelium deposit accumulation. In addition, expression of human CFH also completely protected the mice from developing kidney abnormalities associated with loss of CFH. These humanized CFH mice present a valuable model for study of the molecular mechanisms of age-related macular degeneration and dense deposit disease and for testing therapeutic targets.
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jin-Dong
authors.initials: JD
authors.lastname: Ding
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Una
authors.initials: U
authors.lastname: Kelly
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael
authors.initials: M
authors.lastname: Landowski
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina; Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Toomey
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Marybeth
authors.initials: M
authors.lastname: Groelle
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Chelsey
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Smith
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mikael
authors.initials: M
authors.lastname: Klingeborn
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Terry
authors.initials: T
authors.lastname: Singhapricha
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Haixiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Frank
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina; Department of Cell Biology, Duke University Medical Center, Durham, North Carolina. Electronic address: bowes007@duke.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bowes Rickman
mesh_terms: D000818:Animals; D002829:Choroid / Q000473:pathology; D003176:Complement C3 / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004596:Electroretinography; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012160:Retina / Q000378:metabolism; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000473:pathology; D012590:Sclera / Q000473:pathology; D012756:Sheep
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H