Multi-Modal Proteomic Analysis of Retinal Protein Expression Alterations in a Rat Model of Diabetic Retinopathy

VanGuilder, Heather D.; Bixler, Georgina V.; Kutzler, Lydia; Brucklacher, Robert M.; Bronson, Sarah K.; Kimball, Scot R.; Freeman, Willard M.

doi:10.1371/journal.pone.0016271

Cited by 42 publications

(56 citation statements)

References 81 publications

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“…This group also described an increased expression of αB-crystallin in the cytoplasm of endothelial cells of epiretinal membranes in proliferative DR where it co-localized with VEGF (Dong et al, 2012). Several other reports in animal models of DR confirm an increase in αA- and/or αB-crystallin in the retina (VanGuilder et al, 2011; Kandpal et al, 2012). …”

Section: Changes In αB-crystallin Expression In Retina and Relatiomentioning

confidence: 80%

Novel roles for α-crystallins in retinal function and disease

Kannan

Sreekumar

Hinton

2012

Progress in Retinal and Eye Research

111

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α-Crystallins are key members of the superfamily of small heat shock proteins that have been studied in detail in the ocular lens. Recently, novel functions for α-crystallins have been identified in the retina and in the retinal pigmented epithelium (RPE). αB-Crystallin has been localized to multiple compartments and organelles including mitochondria, golgi apparatus, endoplasmic reticulum and nucleus. α-Crystallins are regulated by oxidative and endoplasmic reticulum stress, and inhibit apoptosis-induced cell death. α-Crystallins interact with a large number of proteins that include other crystallins, and apoptotic, cytoskeletal, inflammatory, signaling, angiogenic, and growth factor molecules. Studies with RPE from αB-crystallin deficient mice have shown that αB-crystallin supports retinal and choroidal angiogenesis through its interaction with vascular endothelial growth factor. αB-Crystallin has also been shown to have novel functions in the extracellular space. In RPE, αB-crystallin is released from the apical surface in exosomes where it accumulates in the interphotoreceptor matrix and may function to protect neighboring cells. In other systems administration of exogenous recombinant αB-crystallin has been shown to be anti-inflammatory. Another newly described function of αB-crystallin is its ability to inhibit β-amyloid fibril formation. α-Crystallin mini-chaperone peptides have been identified that elicit anti-apoptotic function in addition to being efficient chaperones. Generation of liposomal particles and other modes of nanoencapsulation of these minipeptides could offer great therapeutic advantage in ocular delivery for a wide variety of retinal degenerative, inflammatory and vascular diseases including age related macular degeneration and diabetic retinopathy.

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Section: Changes In αB-crystallin Expression In Retina and Relatiomentioning

confidence: 80%

Novel roles for α-crystallins in retinal function and disease

Kannan

Sreekumar

Hinton

2012

Progress in Retinal and Eye Research

111

View full text Add to dashboard Cite

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“…We again utilized a targeted biomarker approach, performing western blot analysis on a series of gene products that did not respond to insulin in a previous proteomic screen. 8 Protein levels of galectin-3 (Lgals3), STAT3, and annexin V have been shown to be upregulated in diabetic animals, yet insulin therapy does not significantly rescue this effect. 8 We found that both free and nanoliposomal minocycline were able to return STAT3 to prediabetic levels (Figure 7).…”

Section: Resultsmentioning

confidence: 99%

“…8 Protein levels of galectin-3 (Lgals3), STAT3, and annexin V have been shown to be upregulated in diabetic animals, yet insulin therapy does not significantly rescue this effect. 8 We found that both free and nanoliposomal minocycline were able to return STAT3 to prediabetic levels (Figure 7). In addition, free minocycline caused galectin-3 to return to prediabetic levels, and liposomal minocycline caused annexin V to return to prediabetic levels.…”

Section: Resultsmentioning

confidence: 99%

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Nanoliposomal minocycline for ocular drug delivery

Kaiser¹,

Imai²,

Haakenson³

et al. 2013

Nanomedicine: Nanotechnology, Biology and Medicine

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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.

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“…Two cohorts of male Sprague-Dawley rats were purchased at 100–125g body mass (Charles River, Wilmington, MA). After one week of quarantine, all rats were fasted overnight and diabetes was induced by intraperitoneal injection of 65mg/kg streptozotocin (STZ; Sigma Aldrich, St. Louis, MO) dissolved in 10mM sodium citrate (pH 4.5) as previously described (Bixler et al, 2011; VanGuilder et al, 2011). Non-diabetic (ND) control rats received the same treatment but were injected with an equal volume of citrate buffer.…”

Section: Methodsmentioning

confidence: 99%

Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

Masser¹,

Starkey²,

Bixler³

et al. 2014

Experimental Eye Research

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Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.

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Multi-Modal Proteomic Analysis of Retinal Protein Expression Alterations in a Rat Model of Diabetic Retinopathy

Cited by 42 publications

References 81 publications

Novel roles for α-crystallins in retinal function and disease

Novel roles for α-crystallins in retinal function and disease

Nanoliposomal minocycline for ocular drug delivery

Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

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