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Mollie Friedlander, Toshihide Kurihara, Peter D. Westenskow, Lea Scheppke, Edith Aguilar, Martin Friedlander; Hypoxic Stress Induces Accelerated Pathological Angiogenesis and Gliosis in a Murine Model of Duchenne Muscular Dystrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4122.
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Duchenne muscular dystrophy (DMD) is carried by an X-linked recessive gene (dystrophin). DMD is an inherited disease causing severe muscle degeneration with an incidence of 1 in 3,000 males. Five isoforms of dystrophin gene products (Dp427p, Dp427c, Dp427m, Dp260, and Dp71) are expressed in the retina. Dp71 is known to be expressed in glial cells (including retinal Muller glia), and functions to anchor water (AQP4) and potassium channels (Kir4.1) to cell membranes. We hypothesized that dystrophin isoforms may function to maintain fluid homeostasis when stressed. In this study, we examined the retinal phenotypes of MDX3CV mutant mice, which do not generate any of the dystrophin isoforms, after exposing them to hypoxic stress.
Breeding pairs of MDX3CV mutant mice were established to obtain phenotypic mutant mice and control in the same litters. Control and mutant mice were exposed to 75% oxygen from postnatal day 7 (P7) to P12 to induce oxygen-induced retinopathy (OIR). Pathological angiogenesis and gliosis were evaluated in littermates using immunohistochemistry on whole mount retinal preparations and cryosectioned retinas. Real-time quantitative PCR analyses were performed to identify any genes dysregulated in the mutants during hypoxic stress.
Significantly more neovascular tufts (p<0.01) and activated Muller glia (p<0.05) are observed in P17 MDX3CV mice compared with control littermates. Additionally, a significant downregulation of aquaporin 4 (p<0.05) and Kir4.1 (p<0.01) genes was observed in mutants compared to controls.
These results suggest that dystrophin isoforms in the retina maintain proper water balance, suppress Muller glia activation, and prevent pathological angiogenesis under condition of hypoxic stress.
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