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TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations.

Joussen AM, Doehmen S, Le ML, Koizumi K, Radetzky S, Krohne TU, Poulaki V, Semkova I, Kociok N - Mol. Vis. (2009)

Bottom Line: Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls.Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes.Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Heinrich Heine University, Duesseldorf, Germany. JoussenA@googlemail.com

ABSTRACT

Purpose: The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor alpha (TNF-alpha) in diabetes-related histopathological changes in two relevant rodent models.

Methods: In short-term studies, Long-Evans rats with streptozotocin-induced diabetes were treated with or without the TNF-alpha inhibitor, etanercept. For long-term studies, tumor necrosis factor receptor I (TNF-RI)-deficient mice and TNF-RII-deficient mice, as well as C57/Bl6 wild-type mice, were fed 30% galactose for up to 20 months. The retinal histopathological alterations of hypergalactosemia were analyzed in trypsin digest preparations. Endothelial cell injury and apoptosis in rat retinas were evaluated by propidium iodide, TUNEL, CytoDeath staining, and DNA fragmentation ELISA. Caspase 3 and 8 activity was evaluated by immunoblotting and quantitative enzymatic activity assay.

Results: Etanercept suppressed caspase activation, retinal cell injury, and apoptosis in short-term diabetic rats. Pericyte and endothelial cell loss were also reduced in long-term hypergalactosemic mice. Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls.

Conclusions: Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes. Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

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Related in: MedlinePlus

Representative images of the capillary bed in galacosemic animals and age-matched controls. Histopathological changes were investigated in galactosemic TNF-RI−/− and TNF-RII−/− mice and their respective wild-type controls by trypsin digestion of the retinas. Representative images of the capillary bed of trypsin digested retinas in age-matched controls (left column) and galactosemic animals (right column) are shown.
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f8: Representative images of the capillary bed in galacosemic animals and age-matched controls. Histopathological changes were investigated in galactosemic TNF-RI−/− and TNF-RII−/− mice and their respective wild-type controls by trypsin digestion of the retinas. Representative images of the capillary bed of trypsin digested retinas in age-matched controls (left column) and galactosemic animals (right column) are shown.

Mentions: Furthermore, the formation of acellular capillaries per retina was quantified as described previously [4,6,19,28]. In all groups of animals fed with normal chow, five or fewer acellular capillaries per retina were found: C57/BL6 3.25±0.5, Rp55−/− 2.25±0.5, and Rp75−/− 2.5±0.57. In all strains, the number of acellular capillaries increased with the duration of galactose feeding. The number of acellular capillaries showed an approximately ninefold increase after 20 months of hypergalactosemia (Figure 7C) and a decrease in TNFR-deficient mice. Representative images of the capillary bed of trypsin digested retinas in galactosemic animals and age-matched controls are presented in Figure 8. The loss of endothelial cells and pericytes as well as the acellular capillaries in the retinas of 16 months galactosemic animals can be seen clearly.


TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations.

Joussen AM, Doehmen S, Le ML, Koizumi K, Radetzky S, Krohne TU, Poulaki V, Semkova I, Kociok N - Mol. Vis. (2009)

Representative images of the capillary bed in galacosemic animals and age-matched controls. Histopathological changes were investigated in galactosemic TNF-RI−/− and TNF-RII−/− mice and their respective wild-type controls by trypsin digestion of the retinas. Representative images of the capillary bed of trypsin digested retinas in age-matched controls (left column) and galactosemic animals (right column) are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2716944&req=5

f8: Representative images of the capillary bed in galacosemic animals and age-matched controls. Histopathological changes were investigated in galactosemic TNF-RI−/− and TNF-RII−/− mice and their respective wild-type controls by trypsin digestion of the retinas. Representative images of the capillary bed of trypsin digested retinas in age-matched controls (left column) and galactosemic animals (right column) are shown.
Mentions: Furthermore, the formation of acellular capillaries per retina was quantified as described previously [4,6,19,28]. In all groups of animals fed with normal chow, five or fewer acellular capillaries per retina were found: C57/BL6 3.25±0.5, Rp55−/− 2.25±0.5, and Rp75−/− 2.5±0.57. In all strains, the number of acellular capillaries increased with the duration of galactose feeding. The number of acellular capillaries showed an approximately ninefold increase after 20 months of hypergalactosemia (Figure 7C) and a decrease in TNFR-deficient mice. Representative images of the capillary bed of trypsin digested retinas in galactosemic animals and age-matched controls are presented in Figure 8. The loss of endothelial cells and pericytes as well as the acellular capillaries in the retinas of 16 months galactosemic animals can be seen clearly.

Bottom Line: Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls.Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes.Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Heinrich Heine University, Duesseldorf, Germany. JoussenA@googlemail.com

ABSTRACT

Purpose: The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor alpha (TNF-alpha) in diabetes-related histopathological changes in two relevant rodent models.

Methods: In short-term studies, Long-Evans rats with streptozotocin-induced diabetes were treated with or without the TNF-alpha inhibitor, etanercept. For long-term studies, tumor necrosis factor receptor I (TNF-RI)-deficient mice and TNF-RII-deficient mice, as well as C57/Bl6 wild-type mice, were fed 30% galactose for up to 20 months. The retinal histopathological alterations of hypergalactosemia were analyzed in trypsin digest preparations. Endothelial cell injury and apoptosis in rat retinas were evaluated by propidium iodide, TUNEL, CytoDeath staining, and DNA fragmentation ELISA. Caspase 3 and 8 activity was evaluated by immunoblotting and quantitative enzymatic activity assay.

Results: Etanercept suppressed caspase activation, retinal cell injury, and apoptosis in short-term diabetic rats. Pericyte and endothelial cell loss were also reduced in long-term hypergalactosemic mice. Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls.

Conclusions: Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes. Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

Show MeSH
Related in: MedlinePlus