TY - JOUR
T1 - Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration
AU - Ibrahim, Ahmed S.
AU - Mander, Suchreet
AU - Hussein, Khaled A.
AU - Elsherbiny, Nehal M.
AU - Smith, Sylvia B.
AU - Al-Shabrawey, Mohamed
AU - Tawfik, Amany
N1 - Funding Information:
This work was supported by startup funds from the Dental College of Georgia, Augusta University, a pilot project grant from the James and Jean Culver Vision Discovery Institute (VDI) and 5R01EY023315-02 to M. Al-Shabrawey
PY - 2016
Y1 - 2016
N2 - The disruption of retinal pigment epithelial (RPE) function and the degeneration of photoreceptors are cardinal features of age related macular degeneration (AMD); however there are still gaps in our understanding of underlying biological processes. Excess homocysteine (Hcy) has been reported to be elevated in plasma of patients with AMD. This study aimed to evaluate the direct effect of hyperhomocysteinemia (HHcy) on structure and function of RPE. Initial studies in a mouse model of HHcy, in which cystathionine-β-synthase (cbs) was deficient, revealed abnormal RPE cell morphology with features similar to that of AMD upon optical coherence tomography (OCT), fluorescein angiography (FA), histological, and electron microscopic examinations. These features include atrophy, vacuolization, hypopigmentation, thickened basal laminar membrane, hyporeflective lucency, choroidal neovascularization (CNV), and disturbed RPE-photoreceptor relationship. Furthermore, intravitreal injection of Hcy per se in normal wild type (WT) mice resulted in diffuse hyper-fluorescence, albumin leakage, and CNV in the area of RPE. In vitro experiments on ARPE-19 showed that Hcy dose-dependently reduced tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance, and impaired phagocytic activity. Collectively, our results demonstrated unreported effects of excess Hcy levels on RPE structure and function that lead to the development of AMD-like features.
AB - The disruption of retinal pigment epithelial (RPE) function and the degeneration of photoreceptors are cardinal features of age related macular degeneration (AMD); however there are still gaps in our understanding of underlying biological processes. Excess homocysteine (Hcy) has been reported to be elevated in plasma of patients with AMD. This study aimed to evaluate the direct effect of hyperhomocysteinemia (HHcy) on structure and function of RPE. Initial studies in a mouse model of HHcy, in which cystathionine-β-synthase (cbs) was deficient, revealed abnormal RPE cell morphology with features similar to that of AMD upon optical coherence tomography (OCT), fluorescein angiography (FA), histological, and electron microscopic examinations. These features include atrophy, vacuolization, hypopigmentation, thickened basal laminar membrane, hyporeflective lucency, choroidal neovascularization (CNV), and disturbed RPE-photoreceptor relationship. Furthermore, intravitreal injection of Hcy per se in normal wild type (WT) mice resulted in diffuse hyper-fluorescence, albumin leakage, and CNV in the area of RPE. In vitro experiments on ARPE-19 showed that Hcy dose-dependently reduced tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance, and impaired phagocytic activity. Collectively, our results demonstrated unreported effects of excess Hcy levels on RPE structure and function that lead to the development of AMD-like features.
KW - Age related macular degeneration
KW - Cystathionine-β-synthase and mouse
KW - Gerotarget
KW - Hyperhomocysteinemia
KW - Retinal pigment epithelium
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U2 - 10.18632/oncotarget.7384
DO - 10.18632/oncotarget.7384
M3 - Article
C2 - 26885895
AN - SCOPUS:84961638003
SN - 1949-2553
VL - 7
SP - 8532
EP - 8545
JO - Oncotarget
JF - Oncotarget
IS - 8
ER -