Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon.
Hyperglycemia is considered as one of the major determinants in the development of diabetic retinopathy, but the progression of retinopathy resists arrest after hyperglycemia is terminated, suggesting a metabolic memory phenomenon. Diabetes alters the expression of retinal genes, and this continues even after good glycemic control is re-instituted. Since the expression of genes is affected by chromatin structure that is modulated by post-translational modifications of histones, our objective is to investigate the role of histone acetylation in the development of diabetic retinopathy, and in the metabolic memory phenomenon. Streptozotocin-induced rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb >11%) or good glycemic control (GC, GHb <6%) for 12 months, or allowed to be in PC for 6 months followed by in GC for 6 months (PC-GC). On a cellular level, retinal endothelial cells, the target of histopathology of diabetic retinopathy, were incubated in 5 or 20 mM glucose for 4 days. Activities of histone deacetylase (HDAC) and histone acetyltransferase (HAT), and histone acetylation were quantified. Hyperglycemia activated HDAC and increased HDAC1, 2, and 8 gene expressions in the retina and its capillary cells. The activity HAT was compromised and the acetylation of histone H3 was decreased. Termination of hyperglycemia failed to provide any benefits to diabetes-induced changes in retinal HDAC and HAT, and histone H3 remained subnormal. This suggests "in principle" the role of global acetylation of retinal histone H3 in the development of diabetic retinopathy and in the metabolic memory phenomenon associated with its continued progression.
Zhong
Qing
Q
Department of Ophthalmology, Wayne State University, Detroit, Michigan, USA.
Kowluru
Renu A
RA
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000150:complications / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008297:Male; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006657:Histones; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D005947:Glucose