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L. D. Wicker, A. Kasus-Jacobi; Regulation of Retinol Dehydrogenase RDH12 by Light and 4-Hydroxynonenal-Induced Stress. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4397. doi: https://doi.org/.
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The retinol dehydrogenase RDH12 has been linked to severe and early onset rod-cone dystrophy. The physiological role of RDH12 is unclear and we hypothesized that it protects photoreceptor cells from toxic hydroxyl aldehydes such as 4-hydroxynonenal (4-HNE), which are produced during oxidative stress. RDH12 is located in the inner segment of rods and reduces aldehydic substrates (retinaldehydes, 4-HNE, and other short-chain aldehydes) to corresponding alcohols using NADPH as a coenzyme. Here, we investigated the regulation of RDH12 level during normal and acute light stress and in retinal explants exposed to 4-HNE.
We used quantitative RT-PCR and immunoblot analysis to quantify the levels of RDH12 mRNA and protein in mouse retina: 1) at different times during the normal dark/light cycle, 2) at 2, 4, 6, 8, 12, and 24 h of exposure to intense light, and 3) at ½, 1, 2, 4, 6, and 8 h of retinal explants exposure to 200 µM 4-HNE.
We found no or very little regulation of RDH12 at the mRNA level in all conditions tested. However, we found significant changes of RDH12 at the protein level. RDH12 increased sharply during the first hour of the light cycle, remained elevated during the 12 h of light, and then decreased slowly back to its original level during the dark cycle. During exposure to intense light, RDH12 level increased transiently during the first 2 h and then decreased steadily until 8 h of light damage, after which its level stabilized at 50% of its original level. During exposure of retinal explants to 4-HNE, the level of RDH12 protein decreased during the first 4 h and then stabilized at 50% of its original level, suggesting that modification of RDH12 by 4-HNE could be a signal triggering its degradation.
We found that light and 4-HNE stress regulates RDH12 at the protein level. We hypothesize that RDH12 turnover is increased by stress, allowing the clearance of hydroxy aldehydes. When the stress level is moderated, the net effect is an increase of RDH12 level due to increased biosynthesis. Under acute stress situations, the net effect is a decrease of RDH12 due to extended oxidative modification and degradation of the protein. RDH12 plays a crucial role in photoreceptor cell survival; therefore understanding the regulation of its protein level by the environment is of clinical importance.
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