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: Jin-Dong Ding, Una Kelly, Michael Landowski, Christopher B Toomey, Marybeth Groelle, Chelsey Miller, Stephanie G Smith, Mikael Klingeborn, Terry Singhapricha, Haixiang Jiang, Michael M Frank, Catherine Bowes Rickman
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 1 Pg. 29-42 (Jan 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25447048 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CFH protein, human
• Complement C3
• Complement Factor H

Topics

• Animals
• Choroid (pathology)
• Complement C3 (metabolism)
• Complement Factor H (genetics, metabolism)
• Crosses, Genetic
• Electroretinography
• Humans
• Kidney Diseases (genetics, pathology)
• Macular Degeneration (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Retina (metabolism)
• Retinal Diseases (genetics, pathology)
• Retinal Pigment Epithelium (pathology)
• Sclera (pathology)
• Sheep