Retinal basal laminar deposits in complement fH/fP mouse model of dense deposit disease

Song, Delu; Mohammed, Imran; Bhuyan, Rupak; Miwa, Takashi; Williams, Allison Lesher; Gullipalli, Damodar; Sato, Sayaka; Song, Ying; Dunaief, Joshua L.; Song, Wen-Chao

Abstract

Purpose: Dense deposit disease (DDD) is caused by dysregulation of the alternative pathway of the complement cascade and characterized by electron-dense deposits in the kidney glomerular basement membrane (GBM) and drusen in Bruch's membrane (BrM). Complement factor H (fH) and factor properdin (fP) regulate complement activation; fH inhibits alternative pathway (AP) activation, whereas fP promotes it. We report pathologic changes in eyes of an fH and fP double-mutant mouse, which we previously showed have dense deposits in the GBM and early mortality from nephropathy.

Methods: fHm/m, fP−/−, and fHm/m/fP−/− mice were generated on a C57BL/6–129J background. Fundus imaging at 8 weeks of age was followed by analysis via light and electron microscopy. Retinal function was assessed by electroretinography (ERG). Complement levels and localization were tested by immunohistochemistry and ELISA. Retinas of fHm/m/fP−/− mice treated with intraperitoneal injections of an anti-C5 antibody were compared to those of age- and genotype-matched mice injected with an isotype control antibody.

Results: fHm/m/fP−/− mice suffered early-onset retinal hypopigmented spots detected using in vivo retinal photography, and histologic examination showed basal laminar deposits (BLamD), degeneration of the photoreceptors, and RPE vacuolization. ERG showed diminished retinal function. The anti-C5 antibody was retina-protective.

Conclusions: This unique mouse represents a new model of complement-mediated rapid-onset DDD, and could be useful in exploring the pathologic changes associated with BLamD in age-related macular degeneration.

Citation

Song, D., Mohammed, I., Bhuyan, R., Miwa, T., Williams, A. L., Gullipalli, D., …Song, W. (2018). Retinal basal laminar deposits in complement fH/fP mouse model of dense deposit disease. Investigative Ophthalmology & Visual Science, 59(8), 3405-3415. https://doi.org/10.1167/iovs.18-24133

• Journal Article Type: Article
• Acceptance Date: May 25, 2018
• Publication Date: Jul 10, 2018
• Deposit Date: Aug 23, 2018
• Publicly Available Date: Aug 23, 2018
• Journal: Investigative Opthalmology & Visual Science
• Print ISSN: 0146-0404
• Publisher: Association for Research in Vision and Ophthalmology
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 8
• Pages: 3405-3415
• DOI: https://doi.org/10.1167/iovs.18-24133
• Public URL: https://nottingham-repository.worktribe.com/output/1045714
• Publisher URL: https://iovs.arvojournals.org/article.aspx?articleid=2688004