Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.
Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.
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DOI：
10.1371/journal.pone.0162596
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Ablonczy Z
中科院分区：
文献类型：
--
作者：
Desjardins D;Liu Y;Crosson CE;Ablonczy Z
在糖尿病患者中，黄斑水肿是导致视力丧失的主要原因。这种情况对胰岛素治疗是无效的，并被归因于代谢记忆。视网膜色素上皮(RPE)是维持视网膜液体平衡的中心，这一功能受到晚期糖基化终产物受体(RAGE)激活的影响。在这里，我们提供的证据表明，急性给予RAGE激动剂糖化白蛋白(GALB)或血管内皮生长因子(VEGF)，可增加RPE细胞中组蛋白脱乙酰酶(HDAC)的活性。给予I/II类HDAC抑制剂曲古抑素-A(TSA)，可抑制Galb诱导的RPE跨上皮阻力(体外)和液体转运(体内)的降低。全身性TSA还恢复了亚慢性高血糖大鼠正常的RPE液体转运。GALB和血管内皮细胞生长因子都增加了hdac活性，降低了乙酰微管蛋白的水平。HDAC6相对特异的拮抗剂Tubasatin-A可抑制Galb诱导的RPE细胞抵抗力的改变。这些数据与以下观点一致，即暴露于Galb、血管内皮生长因子或高血糖后的视网膜色素上皮功能障碍与HDAC6活性增加和乙酰-α-微管蛋白减少有关。因此，我们建议抑制RPE中的HDAC6作为一种潜在的治疗方法，以保持高血糖视网膜中正常的液体稳态。
In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina.
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影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
3.7
作者：
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通讯作者：
Hinton DR
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作者：
Dai Y;Wu Z;Wang F;Zhang Z;Yu M
通讯作者：
Yu M
影响因子：
5.1
作者：
Kakehashi, Akihiro;Inoda, Shigeru;Kanazawa, Yasunori
通讯作者：
Kanazawa, Yasunori
影响因子：
4.4
作者：
Ablonczy, Zsolt;Dahrouj, Mohammad;Crosson, Craig E.
通讯作者：
Crosson, Craig E.