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Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon.

ABSTRACT: 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.

SUBMITTER: Zhong Q

PROVIDER: S-EPMC2907436 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon.

Zhong Qing Q Kowluru Renu A RA

Journal of cellular biochemistry 20100801 6

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 ...[more]

PMID: 20564224

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Project description:Genome-wide association studies have suggested an association between a previously uncharacterized gene, FAM18B, and diabetic retinopathy. This study explores the role of FAM18B in diabetic retinopathy. An improved understanding of FAM18B could yield important insights into the pathogenesis of this sight-threatening complication of diabetes mellitus.Postmortem human eyes were examined with immunohistochemistry and immunofluorescence for the presence of FAM18B. Expression of FAM18B in primary human retinal microvascular endothelial cells (HRMECs) exposed to hyperglycemia, vascular endothelial growth factor (VEGF), or advanced glycation end products (AGEs) was determined with quantitative reverse-transcription PCR (qRT-PCR) and/or western blot. The role of FAM18B in regulating human retinal microvascular endothelial cell viability, migration, and endothelial tube formation was determined following RNAi-mediated knockdown of FAM18B. The presence of FAM18B was determined with qRT-PCR in CD34+/VEGFR2+ mononuclear cells isolated from a cohort of 17 diabetic subjects with and without diabetic retinopathy.Immunohistochemistry and immunofluorescence demonstrated the presence of FAM18B in the human retina with prominent vascular staining. Hyperglycemia, VEGF, and AGEs downregulated the expression of FAM18B in HRMECs. RNAi-mediated knockdown of FAM18B in HRMECs contributed to enhanced migration and tube formation as well as exacerbating the hyperglycemia-induced decrease in HRMEC viability. The enhanced migration, tube formation, and decrease in the viability of HRMECs as a result of FAM18B downregulation was reversed with pyrrolidine dithiocarbamate (PDTC), a specific nuclear factor-kappa B (NF-?B) inhibitor. CD34+/VEGFR2+ mononuclear cells from subjects with proliferative diabetic retinopathy demonstrated significantly reduced mRNA expression of FAM18B compared to diabetic subjects without retinopathy.FAM18B is expressed in the retina. Diabetic culture conditions decrease the expression of FAM18B in HRMECs. The downregulation of FAM18B by siRNA in HRMECs results in enhanced migration and tube formation, but also exacerbates the hyperglycemia-induced decrease in HRMEC viability. The pathogenic changes observed in HRMECs as a result of FAM18B downregulation were reversed with PDTC, a specific NF-?B inhibitor. This study is the first to demonstrate a potential role for FAM18B in the pathogenesis of diabetic retinopathy.

Dataset Information

Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon.

Publications

Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon.

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