Müller Glial Expression of REDD1 Is Required for Retinal Neurodegeneration and Visual Dysfunction in Diabetic Mice.
Müller Glial Expression of REDD1 Is Required for Retinal Neurodegeneration and Visual Dysfunction in Diabetic Mice.
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临床研究支持在发育和DNA损伤反应1 （REDD1）中调节的蛋白在缺血性视网膜并发症中的作用。为了更好地了解REDD1如何促进视网膜病理，我们检查了人类单细胞测序数据集，发现REDD1表达的特异性与视网膜<s:1> ller胶质细胞标志物一致。因此，我们研究了REDD1在突触神经胶质中的特异性表达与糖尿病诱导的视网膜病理有关的假设。m<s:1> ller胶质细胞特异性REDD1敲除（REDD1- mgko）小鼠的视网膜表现出REDD1转录物和蛋白表达的急剧衰减。在链脲佐菌素诱导的糖尿病对照小鼠视网膜中，REDD1蛋白的表达随着氧化应激的增加而增强。在糖尿病小鼠视网膜中，与糖尿病对照组小鼠相比，red1蛋白表达未增加，氧化应激降低。在糖尿病小鼠视网膜内的m<s:1> ller胶质细胞和暴露于高血糖条件下的人m<s:1> ller细胞培养物中，REDD1对于胶质细胞形成标志物胶质纤维酸性蛋白的表达增加是必需的。REDD1缺失预防胶质瘤的作用与抑制氧化应激有关，需要抗氧化转录因子核因子红细胞2相关因子2 （Nrf2）的参与。与糖尿病对照组小鼠相比，糖尿病小鼠REDD1-mgKO没有表现出视网膜变薄、视网膜神经节细胞层内神经变性标志物增加或视觉功能缺陷。总的来说，这些发现支持了<s:1> ller胶质细胞REDD1在视网膜对糖尿病的适应性反应失败（包括胶质细胞增生、神经变性和视力受损）中的关键作用。
Clinical studies support a role for the protein regulated in development and DNA damage response 1 (REDD1) in ischemic retinal complications. To better understand how REDD1 contributes to retinal pathology, we examined human single-cell sequencing data sets and found specificity of REDD1 expression that was consistent with markers of retinal Müller glia. Thus, we investigated the hypothesis that REDD1 expression specifically in Müller glia contributes to diabetes-induced retinal pathology. The retina of Müller glia-specific REDD1 knockout (REDD1-mgKO) mice exhibited dramatic attenuation of REDD1 transcript and protein expression. In the retina of streptozotocin-induced diabetic control mice, REDD1 protein expression was enhanced coincident with an increase in oxidative stress. In the retina of diabetic REDD1-mgKO mice, there was no increase in REDD1 protein expression, and oxidative stress was reduced compared with diabetic control mice. In both Müller glia within the retina of diabetic mice and human Müller cell cultures exposed to hyperglycemic conditions, REDD1 was necessary for increased expression of the gliosis marker glial fibrillary acidic protein. The effect of REDD1 deletion in preventing gliosis was associated with suppression of oxidative stress and required the antioxidant transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2). In contrast to diabetic control mice, diabetic REDD1-mgKO mice did not exhibit retinal thinning, increased markers of neurodegeneration within the retinal ganglion cell layer, or deficits in visual function. Overall, the findings support a key role for Müller glial REDD1 in the failed adaptive response of the retina to diabetes that includes gliosis, neurodegeneration, and impaired vision.
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影响因子：
4.4
作者：
Deliyanti, Devy;Alrashdi, Saeed F.;Wilkinson-Berka, Jennifer L.
通讯作者：
Wilkinson-Berka, Jennifer L.
影响因子：
13.7
作者：
Alasil T;Keane PA;Updike JF;Dustin L;Ouyang Y;Walsh AC;Sadda SR
通讯作者：
Sadda SR
影响因子：
64.5
作者：
Cowan CS;Renner M;De Gennaro M;Gross-Scherf B;Goldblum D;Hou Y;Munz M;Rodrigues TM;Krol J;Szikra T;Cuttat R;Waldt A;Papasaikas P;Diggelmann R;Patino-Alvarez CP;Galliker P;Spirig SE;Pavlinic D;Gerber-Hollbach N;Schuierer S;Srdanovic A;Balogh M;Panero R;Kusnyerik A;Szabo A;Stadler MB;Orgül S;Picelli S;Hasler PW;Hierlemann A;Scholl HPN;Roma G;Nigsch F;Roska B
通讯作者：
Roska B
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
影响因子：
4.2
作者：
Jackson, Gregory R.;Barber, Alistair J.
通讯作者：
Barber, Alistair J.