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D. Zhu, X. Deng, J. Chen, S. J. Ryan, D. R. Hinton; Bmp4 Over-Expression Increases Senescence and Apoptosis of Rpe and Photoreceptor Cells in vivo. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6195.
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RPE senescence and apoptosis are critical features of dry AMD. We previously reported that BMP4 was up-regulated in the RPE and its surrounding tissues of AMD patients and involved in oxidative stress induced RPE senescence in vitro. This study is to further determine whether prolonged BMP4 over-expression in RPE induces RPE senescence and apoptosis in vivo.
Creating Transgenic mouse model: A DNA fragment from the promoter region of human Vitelliform Macular Degeneration (VMD) gene was recombined to drive the expression of mouse BMP4 cDNA transgene. 2). Light exposure: Six month old transgenic and wild type mice were exposed to constant fluorescent light at an intensity of 1200 to 1500 lux for the periods of 1, 2 and 3 weeks with dilated pupils. 3). TUNEL and Senescence-Associated Beta-Galactosidase (SA-β-Gal) assays were used to evaluate retinal apoptosis and senescence. 4). Quantitative RT-PCRwas used to measure BMP4 expression level.
Seven transgenic mouse founder lines were created to over-express BMP4 in RPE. The BMP4 expression level in transgenic RPE was 2-3 times higher than in non-transgenic RPE according to qPCR measurement. Some areas of RPE in 12 month old transgenic retinas exhibited atrophic phenotype characterized by flat cell shape and lost of pigmentation. Many more apoptotic cells were observed in the outer nuclear layer of the transgenic retinas than in non-transgenic retinas among 12 month old mice. The SA-β-Gal staining showed that more senescent RPE and photoreceptor cells were present in transgenic retinas than in non-transgenic retinas. Light exposure accelerated/increased photoreceptor cell death in 6 month old transgenic mice compared to age matched controls.
BMP4 over-expression in mouse RPE increases senescence and apoptosis of RPE and photoreceptor cells in vivo, suggesting that BMP4 may be involved in the RPE dysfunction and apoptosis, which are the characteristic of AMD.
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