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ABSTRACT: We demonstrated previously that pro-survival insulin receptor, PI3K-Akt, and p70 S6K signaling is diminished in models of diabetic retinopathy. As mammalian target of rapamycin (mTOR), an upstream activator of p70 S6Kinase is, in part, regulated by lipid-derived second messengers, such as phosphatidic acid (PA), we sought to determine if diminished mTOR/p70 S6Kinase signaling in diabetic retinas may reflect diminished PA levels.
Alterations in PA mass from retinas of control and streptozotocin-induced diabetic rats were determined by mass spectrometry. The biochemical and biophysical mechanisms underlying the actions of PA on insulin-activated mTOR/p70 S6Kinase signaling were determined using R28 retinal neuronal cells.
We demonstrate a significant decrease in PA in R28 retinal neuronal cells exposed to hyperglycemia as well as in streptozotocin-induced diabetic rat retinas. Exogenous PA augmented insulin-induced protection from interleukin-1β-induced apoptosis. Moreover, exogenous PA and insulin cooperatively activated mTOR survival pathways in R28 neuronal cultures. Exogenous PA colocalized with activated mTOR/p70 S6kinase signaling elements within lipid microdomains. The biochemical consequences of this biophysical mechanism is reflected by differential phosphorylation of tuberin at threonine 1462 and serine 1798, respectively, by PA and insulin, which reduce this suppressor of mTOR/S6Kinase signaling within lipid microdomains.
These results identify PA-enriched microdomains as a putative lipid-based signaling element responsible for mTOR-dependent retinal neuronal survival. Moreover, diabetic retinal neuronal apoptosis may reflect diminished PA mass. Elevating PA concentrations and restoring mTOR signaling may be an effective therapeutic modality to reduce neuronal cell death in diabetic retinopathy.
Investigative ophthalmology & visual science 09/2012; 53(11):7257-67. · 3.43 Impact Factor
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New England Journal of Medicine 03/2012; 366(13):1227-39. · 53.30 Impact Factor
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James M Kaiser,
Hisanori Imai,
Jeremy K Haakenson,
Robert M Brucklacher,
Todd E Fox,
Sriram S Shanmugavelandy,
Kellee A Unrath,
Michelle M Pedersen,
Pingqi Dai,
Willard M Freeman,
Sarah K Bronson, Thomas W Gardner,
Mark Kester
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ABSTRACT: Nanoliposomal technology is a promising drug delivery system that could be employed to improve the pharmacokinetic properties of clearance and distribution in ocular drug delivery to the retina. We developed a nanoscale version of an anionic, cholesterol-fusing liposome that can encapsulate therapeutic levels of minocycline capable of drug delivery. We demonstrate that size extrusion followed by size-exclusion chromatography can form a stable 80-nm liposome that encapsulates minocycline at a concentration of 450 ± 30 μM, which is 2% to 3% of loading material. More importantly, these nontoxic nanoliposomes can then deliver 40% of encapsulated minocycline to the retina after a subconjunctival injection in the STZ model of diabetes. Efficacy of therapeutic drug delivery was assessed via transcriptomic and proteomic biomarker panels. For both the free minocycline and encapsulated minocycline treatments, proinflammatory markers of diabetes were downregulated at both the messenger RNA and protein levels, validating the utility of biomarker panels for the assessment of ocular drug delivery vehicles.
Nanomedicine: nanotechnology, biology, and medicine 03/2012; · 5.44 Impact Factor
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ABSTRACT: To determine the effect of diabetes on inner and outer retinal function in persons with diabetes and no clinically detectable retinopathy or with non-proliferative diabetic retinopathy (NPDR).
Visual function was assessed in 18 adults with normal retinal health, 23 adults with diabetes and 35 adults with NPDR and normal visual acuity. Contrast sensitivity and frequency doubling technology (FDT) sensitivity were used to assess ganglion cell function. Acuity, dark adaptation, light-adapted visual sensitivity and dark-adapted visual sensitivity were measured to evaluate cone and rod photoreceptor visual function. The presence and severity of diabetic retinopathy was determined by grading of 7-field stereoscopic fundus photographs using the Early Treatment Diabetic Retinopathy Study grading system.
Participants with NPDR exhibited impairment of all measured visual functions in comparison with the normal participants. Inner retinal function measured by FDT perimetry was the most impaired visual function for patients with NPDR, with 83% of patients exhibiting clinically significant impairment. Rod photoreceptor function was grossly impaired, with almost half of the patients with NPDR exhibiting significantly impaired dark-adapted visual sensitivity.
Both inner retinal and outer retinal functions exhibited impairment related to NPDR. FDT perimetry and other visual function tests reveal an expanded range of diabetes induced retinal damage even in patients with good visual acuity.
The British journal of ophthalmology 12/2011; 96(5):699-703. · 2.92 Impact Factor
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ABSTRACT: This chapter discusses emerging hydrogel technology for drug delivery to the back of the eye to treat retinal diseases. The
review includes design, characterization and optimization of hydrogels, and advantages and disadvantages of intravitreally
and subconjunctivally administrated hydrogels for retinal therapy. Future direction of hydrogel technology for targeted and
sustained delivery of drugs to the retina for individualized medicine is also laid out.
07/2011: pages 291-304;
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ABSTRACT: This review discusses the pathophysiology of diabetic retinopathy related to direct effects of loss of insulin receptor action and metabolic dysregulation on the retina. The resulting sensory neuropathy can be diagnosed by structural and functional tests in patients with mild nonproliferative diabetic retinopathy. Research teams can collaborate to integrate ocular and systemic factors that impair vision and to design strategies to maintain retinal function in persons with diabetes mellitus. Evolving concepts may lead to inclusion of tests of retinal function in the detection of diabetic retinopathy and neuroprotective strategies to preserve vision for persons with diabetes.
Archives of ophthalmology 02/2011; 129(2):230-5. · 3.86 Impact Factor
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ABSTRACT: The most striking features of diabetic retinopathy are the vascular abnormalities that are apparent by fundus examination. There is also strong evidence that diabetes causes apoptosis of neural and vascular cells in the retina. Thus, there is good reason to define diabetic retinopathy as a form of chronic neurovascular degeneration. In keeping with the gradual onset of retinopathy in humans, the rate of cell loss in the animal models is insidious, even in uncontrolled diabetes. This is not surprising given that a sustained high rate of cell loss without regeneration would soon lead to catastrophic tissue destruction. The consequences of ongoing cell death are difficult to detect, and even the quantification of cumulative cell loss requires painstaking histology and microscopy. This subtle cell loss raises the issue of the relevance of the phenomenon to the progression of diabetic retinopathy and the ultimate loss of vision. Neuronal function may be compromised in advance of apoptosis, contributing to an early deterioration of vision. Here we review some of the evidence supporting apoptotic cell death as a contributing mechanism of diabetic retinopathy, explore some of the potential causes, and discuss the potential links between apoptosis and loss of visual function in diabetic retinopathy.
Investigative ophthalmology & visual science 01/2011; 52(2):1156-63. · 3.43 Impact Factor
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ABSTRACT: Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss.
PLoS ONE 01/2011; 6(10):e26498. · 4.09 Impact Factor
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ABSTRACT: Neuronal cell death is an early pathological feature of diabetic retinopathy. We showed previously that insulin receptor signaling is diminished in retinas of animal models of diabetes and that downstream Akt signaling is involved in insulin-mediated retinal neuronal survival. Therefore, further understanding of the mechanisms by which retinal insulin receptor signaling is regulated could have therapeutic implications for neuronal cell death in diabetes. Here, we investigate the role of cholesterol-enriched membrane microdomains to regulate PKC-mediated inhibition of Akt-dependent insulin signaling in R28 retinal neurons. We demonstrate that PKC activation with either a phorbol ester or exogenous application of diacylglycerides impairs insulin-induced Akt activation, whereas PKC inhibition augments insulin-induced Akt activation. To investigate the mechanism by which PKC impairs insulin-stimulated Akt activity, we assessed various upstream mediators of Akt signaling. PKC activation did not alter the tyrosine phosphorylation of the insulin receptor or IRS-2. Additionally, PKC activation did not impair phosphatidylinositol 3-kinase activity, phosphoinositide-dependent kinase phosphorylation, lipid phosphatase (PTEN), or protein phosphatase 2A activities. Thus, we next investigated a biophysical mechanism by which insulin signaling could be disrupted and found that disruption of lipid microdomains via cholesterol depletion blocks insulin-induced Akt activation and reduces insulin receptor tyrosine phosphorylation. We also demonstrated that insulin localizes phosphorylated Akt to lipid microdomains and that PMA reduces phosphorylated Akt. In addition, PMA localizes and recruits PKC isotypes to these cholesterol-enriched microdomains. Taken together, these results demonstrate that both insulin-stimulated Akt signaling and PKC-induced inhibition of Akt signaling depend on cholesterol-enriched membrane microdomains, thus suggesting a putative biophysical mechanism underlying insulin resistance in diabetic retinopathy.
AJP Endocrinology and Metabolism 01/2011; 300(3):E600-9. · 4.75 Impact Factor
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ABSTRACT: Vascular endothelial growth factor (VEGF) contributes to diabetic retinopathy, but control of its expression is not well understood. Here, we tested the hypothesis that hyperglycemia mediates induction of VEGF expression in a eukaryotic initiation factor 4E (eIF4E) binding protein (4E-BP) 1 and 2 dependent manner.
The retina was harvested from control and type 1 diabetic rats and mice and analyzed for VEGF mRNA and protein expression as well as biomarkers of translational control mechanisms. Similar analyses were performed in Müller cell cultures exposed to hyperglycemic conditions. The effect of 4E-BP1 and 4E-BP2 gene deletion on VEGF expression was examined in mice and in mouse embryo fibroblasts (MEFs).
Whereas VEGF mRNA in the retina remained constant, VEGF expression was increased as early as 2 weeks after the onset of diabetes. Increases in expression of 4E-BP1 protein mirrored those of VEGF and expression of 4E-BP1 mRNA was unchanged. Similar results were observed after 10 h of exposure of cells in culture to hyperglycemic conditions. Importantly, the diabetes-induced increase in VEGF expression was not observed in mice deficient in 4E-BP1 and 4E-BP2, nor in MEFs lacking the two proteins.
Hyperglycemia induces VEGF expression through cap-independent mRNA translation mediated by increased expression of 4E-BP1. Because the VEGF mRNA contains two internal ribosome entry sites, the increased expression is likely a consequence of ribosome loading at these sites. These findings provide new insights into potential targets for treatment of diabetic retinopathy.
Diabetes 09/2010; 59(9):2107-16. · 8.29 Impact Factor
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ABSTRACT: Purpose: To assess the relationship between visual acuity (VA) and diabetic macular oedema (DMO) in relation to the location of retinal thickening and the severity and duration of central macular thickening.Methods: Data from 584 eyes in 340 placebo-treated patients in the 3-years-long Protein Kinase C Diabetic Retinopathy Study (PKC-DRS2) trial were used to investigate the relationship between VA and DMO. Eligible eyes had moderately severe to very severe non-proliferative diabetic retinopathy and VA of at least 45 letters on Early Treatment Diabetic Retinopathy Study (ETDRS) charts (Snellen equivalent = 20/125). Diabetic retinopathy and DMO status were assessed using stereo photographs.Results: Nearly one third of study eyes had foveal centre-involving DMO at the start of the trial. Sustained moderate visual loss was found in 36 eyes, most commonly associated with DMO at the centre of the fovea in 73% of eyes. There was a strong relationship (p < 0.001) between foveal centre involvement with DMO and mean VA. Mean VA decreased with increasing retinal thickness at the centre (p < 0.001) and increasing duration of centre-involving DMO (p < 0.001).Conclusion: This study documents the relationship between duration of DMO and progressive vision loss, and the key role of central foveal involvement in patients with diabetic retinopathy. These data will help to develop future strategies to prevent vision loss.
Acta ophthalmologica 10/2009; 87(7):709 - 713. · 2.44 Impact Factor
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ABSTRACT: To assess the relationship between visual acuity (VA) and diabetic macular oedema (DMO) in relation to the location of retinal thickening and the severity and duration of central macular thickening.
Data from 584 eyes in 340 placebo-treated patients in the 3-years-long Protein Kinase C Diabetic Retinopathy Study (PKC-DRS2) trial were used to investigate the relationship between VA and DMO. Eligible eyes had moderately severe to very severe non-proliferative diabetic retinopathy and VA of at least 45 letters on Early Treatment Diabetic Retinopathy Study (ETDRS) charts (Snellen equivalent = 20/125). Diabetic retinopathy and DMO status were assessed using stereo photographs.
Nearly one third of study eyes had foveal centre-involving DMO at the start of the trial. Sustained moderate visual loss was found in 36 eyes, most commonly associated with DMO at the centre of the fovea in 73% of eyes. There was a strong relationship (p < 0.001) between foveal centre involvement with DMO and mean VA. Mean VA decreased with increasing retinal thickness at the centre (p < 0.001) and increasing duration of centre-involving DMO (p < 0.001).
This study documents the relationship between duration of DMO and progressive vision loss, and the key role of central foveal involvement in patients with diabetic retinopathy. These data will help to develop future strategies to prevent vision loss.
Acta ophthalmologica 10/2009; 87(7):709-13. · 2.44 Impact Factor
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ABSTRACT: The objective of this work is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin to the retina to prevent and treat retinal neurovascular degeneration such as diabetic retinopathy. The hydrogels are synthesized by UV photopolymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-(2-hydroxyetheyl methacrylate) units (Dex-lactateHEMA) in 25:75 (v:v) ethanol:water mixture solvent. Insulin is loaded into the hydrogels during the synthesis process with loading efficiency up to 98%. The hydrogels can release biologically active insulin in vitro for at least one week and the release kinetics can be modulated by varying the ratio between NIPAAm and Dex-lactateHEMA and altering the physical size of the hydrogels. The hydrogels are not toxic to R28 retinal neuron cells in culture medium with 100% cell viability. The hydrogels can be implanted under the conjunctiva without causing adverse effects to the retina based on hematoxylin and eosin stain, immunostaining for microglial cell activation, and electroretinography. These subconjunctivally implantable hydrogels have potential for long-term periocular delivery of insulin or other drugs to treat diabetic retinopathy and other retinal diseases.
Biomaterials 09/2009; 30(33):6541-7. · 7.40 Impact Factor
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ABSTRACT: We present a novel approach that combines MALDI-TOF profile analysis and bioinformatics-based inclusion criteria to comprehensively predict phosphorylation sites on a single protein of interest from limiting sample. It is technologically difficult to unambiguously identify phosphorylated residues, as many physiologically important phosphorylation sites are of too low abundance in vivo to be unambiguously assigned by mass spectrometry. Conversely, phosphorylation site prediction algorithms, while increasingly accurate, nevertheless overestimate the number of phosphorylation sites. In this study, we show that MODICAS, an MS data management and analysis tool, can be effectively merged with the bioinformatics attributes of residue conservation and phosphosite prediction to generate a short list of putative phosphorylation sites that can be subsequently verified by additional methodologies such as phosphospecific antibodies or mutational analysis. Therefore, the combination of MODICAS driven MS data analysis with bioinformatics-based filtering represents a substantial increase in the ability to putatively identify physiologically relevant phosphosites from limited starting material.
Journal of Proteome Research 02/2009; 8(2):798-807. · 5.11 Impact Factor
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ABSTRACT: Diabetic retinopathy (DR) is a neurodegenerative and microvascular disease resulting in functional and structural changes of all cell types in the retina. Several mechanisms for neuroretinal homeostasis, including the blood-retinal barrier, normal metabolite delivery into the retina, and the effect of neurotrophins for the retina, are impaired in DR. However, it is still not clear which components are most important for the development of DR and which may be most useful as therapeutic targets. In this chapter, we summarize the evidence for the neurodegeneration in DR and review normal mechanisms for maintenance of postmitotic cells in the retina and alterations in normal maintenance pathways in DR with emphasis on 'neuroprotection'. Finally, we discuss current neuroprotective strategies and future directions for the treatment of DR.
Developments in ophthalmology 02/2009; 44:56-68.
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ABSTRACT: Interleukin-(IL)1beta expression is increased in the retina during a variety of diseases involving the death of retinal neurons and contributes to neurodegenerative processes through an unknown mechanism. This study was conducted to examine the effects of IL-1beta on the metabolism and viability of RGC-5 and R28 retinal neuronal cells.
Cellular reductive capacity was evaluated using WST-1 tetrazolium salt. Mitochondrial transmembrane potential was determined by JC-1 fluorescence. Cellular ATP levels were measured with a luciferase assay. Caspase-3/7 activation was detected with a DEVDase activity assay. Cell death and lysis was evaluated by measuring release of lactate dehydrogenase (LDH). Glycolysis was assessed by measuring glucose disappearance and lactate appearance in cell culture medium. Cellular respiration was followed polarographically.
IL-1beta treatment caused a pronounced decrease in cellular reductive potential. IL-1beta caused depletion of intracellular ATP, loss of mitochondrial transmembrane potential, caspase-3/7 activation, and LDH release. IL-1beta treatment increased rates of glucose utilization and lactate production. The cells were partially protected from IL-1beta toxicity by ample ambient glucose. However, glucose did not block the ability of IL-1beta to cause a decline in mitochondrial transmembrane potential or ATP depletion. IL-1beta decreased oxygen consumption of the R28 cells by nearly half, but did not lower cytochrome c oxidase activity.
The present results suggest that IL-1beta inhibits mitochondrial energy metabolism of these retinal neuronlike cells.
Investigative ophthalmology & visual science 01/2009; 49(12):5581-92. · 3.43 Impact Factor
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ABSTRACT: Diabetic retinopathy is the leading cause of blindness in working age persons. Targeted studies have uncovered several components of the pathophysiology of the disease without unveiling the basic mechanisms. This study describes the use of complementary proteomic and genomic discovery methods that revealed that the proteins of the crystallin superfamily are increased dramatically in early diabetic retinopathy. Orthogonal methods confirmed that the amplitude of the up-regulation is greater than other changes described so far in diabetic retinopathy. A detailed time course study during diabetes showed differential up-regulation of the different isoforms of the crystallins superfamily. alpha- and beta-crystallins were regulated primarily at the translation level, whereas gamma-crystallins were also regulated transcriptionally. We also demonstrated cell-specific patterns of expression of the different crystallins in normal and diabetic rat retinas. In addition, systemic and periocular insulin treatments restored retinal crystallin protein expression during diabetes, indicating effects of phosphoinositide 3-kinase/Akt activity. Altogether this work shows the importance of proteomics discovery methods coupled with targeted approaches to unveil new disease mechanistic details and therapeutic targets.
Molecular & Cellular Proteomics 01/2009; 8(4):767-79. · 7.40 Impact Factor
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ABSTRACT: This article evaluates the current knowledge of the molecular mechanisms by which diabetes ocular and systemic inflammation induce breakdown of the blood-retinal barrier resulting in macular edema. We also summarize the relationship between molecular targets and the use of therapeutic inhibitors in preclinical studies and clinical trials. Further studies are needed to understand the regulation of normal blood-retinal barrier physiology and the relationship between events in animal models of diabetic retinopathy and humans with diabetes.
Current Diabetes Reports 08/2008; 8(4):263-9. · 2.50 Impact Factor
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ABSTRACT: To compare PDGF- and insulin/IGF-1-induced class I(A) PI 3-kinase/Akt survival signaling in normal retinas and retinal ganglion cells (RGCs).
Normal rat retinas and RGC-5 cells were used for (1) immunohistochemical and immunoblot studies to detect PDGF receptor (PDGFR) subtypes and (2) immunoprecipitation, immunoblot, and in vitro lipid kinase assays to determine basal and PDGF-induced class I(A) PI 3-kinase/Akt survival signaling, in comparison with insulin or IGF-1 responses. Furthermore, RGC-5 cells were exposed to broad-spectrum (LY294002) or p110 isoform-selective (PI-103) PI 3-kinase inhibitors (versus Akt inhibitor) to assess the consequent effects on Akt phosphorylation, caspase-3/PARP cleavage, apoptotic phenotype, and cell viability, as a function of serum trophic factors.
PDGFR-alpha and -beta immunoreactivity was observed in rat retinal Müller cells and in the RGC layer and blood vessels, respectively. In addition, PDGFR-alpha and -beta protein expression was observed in RGC-5 cells. Both retinas and RGC-5 cells exhibited a similar pattern of subunit-specific basal class I(A) PI 3-kinase activity, which was stimulated in a temporal and signal-specific manner by PDGF and insulin/IGF-1. Furthermore, RGC-5 cells showed PDGFR-alpha/beta tyrosine phosphorylation that induced the p85alpha regulatory subunit to activate p110alpha/beta-associated class I(A) PI 3-kinase, which in turn enhanced Akt phosphorylation. Exposure of serum-deprived RGC-5 cells to PI 3-kinase or Akt inhibitors increased susceptibility to apoptotic phenotype as revealed by caspase-3 and PARP cleavage.
The present findings provide direct evidence of two distinct modes of retinal class I(A) PI 3-kinase activation that occurs in response to PDGF receptor and insulin/IGF-1 receptor stimulation. PDGF-induced PI 3-kinase/PIP3/Akt axis may provide new therapeutic approaches to ameliorate cell death in diabetic retinopathy and other retinal neurodegenerations.
Investigative ophthalmology & visual science 04/2008; 49(8):3687-98. · 3.43 Impact Factor
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Robert M Brucklacher,
Kruti M Patel,
Heather D Vanguilder,
Georgina V Bixler,
Alistair J Barber,
David A Antonetti,
Cheng-Mao Lin,
Kathryn F LaNoue, Thomas W Gardner,
Sarah K Bronson,
Willard M Freeman
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ABSTRACT: BACKGROUND: Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes. RESULTS: Using the streptozotocin-induced rat model of diabetes, levels of retinal permeability,caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals. CONCLUSION: These changes in permeability, apoptosis, and gene expression provide further evidence of progressive retinal malfunction with increasing duration of diabetes. The specific gene expression changes confirmed in multiple sets of animals indicate that pro-inflammatory, antivascular barrier, and neurodegenerative changes occur in tandem with functional increases in apoptosis and vascular permeability. These responses are shared with the clinically documented inflammatory response in diabetic retinopathy suggesting that this model may be used to test antiinflammatory therapeutics.
BMC Medical Genomics 02/2008; 1:26. · 3.69 Impact Factor
