Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.
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.
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America.
Danielle
D
Desjardins
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America.
Yueying
Y
Liu
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America.
Craig E
CE
Crosson
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America.
Zsolt
Z
Ablonczy
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D006943:Hyperglycemia / Q000201:enzymology / Q000503:physiopathology*; D011817:Rabbits; D051381:Rats; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D042461:Vascular Endothelial Growth Factor A; C012589:trichostatin A; D006655:Histone Deacetylases