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Bogale Aredo, Tao Li, Xiao Chen, Kaiyan Zhang, Biren Zhao, Yu-Guang He, Rafael Ufret-Vincenty; Effect of the 402H Cfh Variant on the Response to Chronic and Acute Retinal Oxidative Stress, and on the Accumulation and Phenotype of Subretinal Microglia. Invest. Ophthalmol. Vis. Sci. 2014;55(13):613.
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© ARVO (1962-2015); The Authors (2016-present)
The “at risk” 402H variant of complement factor H (Cfh) increases the risk of AMD up to 7-fold. On the other hand, oxidative stress appears to play an important role in the pathogenesis of AMD. In this project we explore the role of the 402H Cfh variant in the response of the RPE and retina to both chronic and acute oxidative stress.
We have previously described the generation of a Cfh transgenic mouse model, based on a chimeric transgene consisting of human Cfh SCR6-8 flanked by mouse Cfh SCR1-5 and SCR9-20 (under the ApoE promoter). We have crossed these CfhTg mice to mice deficient in mouse Cfh. In this work we exposed the resulting CfhTg/mCfhKO mice and age-matched C57BL/6J (B6) controls to one model of acute oxidative stress (subretinal injection of H2O2), and three models of chronic oxidative stress (aging to 2 years, immunization with carboxyethyl pyrrole-adducted mouse serum albumin or “CEP”, and hydroquinone supplementation in the diet). We then measured several parameters including: RPE cell damage, accumulation of basal laminar deposits, accumulation of subretinal microglia, phenotype of the subretinal microglia, C3d deposition in Bruch’s membrane, and malondialdehyde (MDA) levels in the retina using ELISA.
CfhTg/mCfhKO mice developed increased accumulation of basal laminar deposits at 2 years of age compared to controls. Also, immunization with CEP-adducted mouse serum albumin led to increased basal laminar deposits in CfhTg/mCfhKO mice. Addition of 0.8% hydroquinone to the diet, led to a dramatic increase in the accumulation of subretinal microglia, and an increase in the deposition of C3d in Bruch’s membrane in CfhTg mice compared to B6 controls. Also, subretinal injection of H2O2 led to increased RPE damage in CfhTg/mCfhKO mice. There was an increased accumulation of subretinal Iba-1+ microglia, including CD16+ cells, and MDA+ cells in aging CfhTg/mCfhKO mice. Finally, there was a significant increase in the level of MDA in the retina of CfhTg/mCfhKO mice compared to B6.
The “at risk” variant of complement factor H leads to increased susceptibility to both chronic and acute oxidative stress in a CfhTg mouse model. There is also an increased inflammatory response in these mice. These findings suggest a mechanism for the increase in AMD risk contributed by the 402H Cfh variant.
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