Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory

Abstract

Diabetic retinopathy resists arrest of its progression after reestablishment of good glycemic control that has followed a profound period of poor glycemic control. This study is to elucidate the role of inflammation in the resistance of retinopathy to arrest after termination of hyperglycemia. Streptozotocin-diabetic rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb>11%) or in good glycemic control (GC, GHb<7%) for 12 months, or allowed to be in PC for six months followed by GC for six additional months. At 12 months, retina was analyzed for pro-inflammatory mediators. Twelve months of PC increased retinal interleukin-1β (IL-1β) mRNA by 2-fold and its protein expressions by 25% compared to the values obtained from normal rat retina. Tumor necrosis factor-α (TNF-α) was elevated approximately 3 fold (both mRNA and protein), and the receptors for IL-1β and TNF-α were increased by 40% each. The concentrations of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were elevated by 40% and 150% respectively, and iNOS transcripts by six fold. Six months of GC that followed six months of PC failed to reverse the elevations in IL-1β, TNFR1 and ICAM-1; and had some beneficial effects on TNF-α, iNOS and VCAM-I, but these mediators remained significantly elevated. However, GC group showed no significant changes in the retinal proinflammatory mediators compared to the normal rats. Failure to reverse retinal inflammatory mediators supports their important role in the resistance of retinopathy to arrest after cessation of hyperglycemia.

Effect of ozone on vascular endothelial growth factor (VEGF) and related inflammatory cytokines in rats with diabetic retinopathy

“…Studies have determined that TNF-a can be an independent influence factor in PDR (Gustavsson et al, 2008), and that VEGF is positively related to ICAM-1, IL-1b, and IL-6 (Cohen et al, 1996;Joussen et al, 2002;Ishida et al, 2003;Moore et al, 2003;Chan et al, 2010). Our study had similar results.…”

MicroRNA-126 Reduces Blood-Retina Barrier Breakdown via the Regulation of VCAM-1 and BCL2L11 in Ischemic Retinopathy

“…After the eyeballs had been dissected, the vitreous and retinas were collected and homogenized in phosphate-buffered saline (PBS). VCAM-1 levels were quantified using enzyme-linked immunosorbent assays (ELISA; R&D Systems, USA) per the manufacturer's instructions using 50 μg of retinal proteins [24] . Briefly, standard solution or the samples together with the soluble VCAM-1 conjugate were added to a 96-well plate which had been precoated with a monoclonal antibody.…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…The involvement of inflammatory processes in the initiation of neurovascular lesions during diabetic retinopathy has received recent attention. Global mRNA expression profiling has highlighted altered expression of proinflammatory cytokines and interrelated pathways, not only in the retinal vessels, but also in the neuroglia [39]. A study in which they investigated the correlation between age, metabolism, and AGEs found that older adults had higher serum concentrations than younger adults; however, the authors also reported that higher AGE concentrations were directly related to dietary intake across all age groups [35].…”

“…Increasing evidence suggests that AGE receptor binding can initiate important signaling pathways involving tyrosine phosphorylation of Janus kinase (JAK)/signal transducers and activators of transcription (STAT) [36], recruitment of phosphatidylinositol 3 kinase to Ras [37], activation of protein kinase C [38], and oxidative stress through NFkB and AP-1 transcription [39]. AGEs interact with cells through several routes.…”