Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in HyperglycemiaReportar como inadecuado




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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.



Autor: Danielle Desjardins, Yueying Liu, Craig E. Crosson, Zsolt Ablonczy

Fuente: http://plos.srce.hr/



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