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.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

“…5 This new role of FH is endorsed by a recent study showing that the expression of human complement FH prevents AMD-like retina damage and kidney abnormalities in aged CFH − / − mice. 31 In conclusion, we have found a new intriguing function of the complement inhibitor FH in apoptotic cell clearance and handling of potential autoantigens (nucleosomes). FH becomes internalized by apoptotic cells and induces intracellular cleavage of C3, which becomes exposed on the cell surface in form of the potent opsonin iC3b, providing an additional removal signal to phagocytes.…”

Complement in removal of the dead – balancing inflammation

“…Thus, the internalization of FH into apoptotic cells with ensuing functional effects may be of particular importance in this tissue. A recent study confirmed the importance of FH in development of AMD and SLE by revealing that the expression of human FH is able to prevent AMD‐like retinal damage and kidney abnormalities in aged CFH −/− mice . The previously suggested relationship between chronic kidney disease and AMD, two seemingly disparate diseases, is thus confirmed.…”

Association between macular degeneration and mild to moderate chronic kidney disease

“…[21] An animal model using transgenic mouse with high expression of CFH, demonstrated a dose-dependent protective effect in the function and structure of both eye and renal abnormalities. [22] In addition, the sharing of common cardiometabolic risks (hypertension, diabetes, dyslipidemia, and tobacco) [23] and pathogenic pathways (atherosclerosis, endothelial dysfunction, oxidative stress, inflammation, altered genetic polymorphisms, complement system dysfunction, and Klotho gene pathway) between these 2 diseases strengthens the supposition of this association. [3–5,8] Clinically, this association has been demonstrated from findings of several epidemiological studies, such as the Blue Mountains Eye Study, [9] case–control subset study of NHANES III, [10] and the Beaver Dam Eye Study.…”