TNFalpha is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis.

Abstract

PURPOSE:

Blood-retinal barrier [BRB] breakdown, characteristic of diabetic retinopathy (DR), is believed to depend on inflammation and apoptosis. Retinal inflammation is almost completely suppressed in the absence of TNFα, which is also associated with apoptosis. This study was conducted to determine the role of TNFα in these diabetic complications.

METHODS:

Diabetes was induced with streptozotocin in Tnfa knockout (KO) mice, to provide a chemical model of diabetes, and Tnfa (KO) mice were crossed with Ins2(Akita) mice to generate a genetic model, with both models being devoid of TNFα. The BRB was assessed at 1, 1.5, 3, and 6 months. Leukostasis was assessed using FITC-conjugated ConA to label leukocytes. Apoptosis was assessed with TUNEL and activated caspase-3 staining. PECAM1 identified endothelial cells, and SMA identified pericytes.

RESULTS:

At 1 month of diabetes, the absence of TNFα had no effect on DR-associated BRB breakdown, even though it prevented retinal leukostasis, demonstrating that neither TNFα nor inflammation is essential for early BRB breakdown in DR in either model of diabetes. At 3 months of diabetes, BRB breakdown was significantly suppressed and at 6 months, it was completely prevented in the absence of TNFα in both models, showing that TNFα is essential for progressive BRB breakdown. DR-mediated apoptosis in the retina, which appears to involve endothelial cells, pericytes, and neurons, was inhibited in the absence of TNFα in both models.

CONCLUSIONS:

Although neither TNFα nor inflammation is necessary for early BRB breakdown in DR, TNFα is critical for later complications and would be a good therapeutic target for the prevention of the progressive BRB breakdown, retinal leukostasis, and apoptosis associated with DR.

• Authors: Hu Huang, Jarel K Gandhi, Xiufeng Zhong, Yanhong Wei, Junsong Gong, Elia J Duh, Stanley A Vinores
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 3 Pg. 1336-44 (Mar 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 21212173 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Platelet Endothelial Cell Adhesion Molecule-1
• Tumor Necrosis Factor-alpha
• Casp3 protein, mouse
• Caspase 3

Topics

• Actins (metabolism)
• Animals
• Apoptosis
• Blood-Retinal Barrier (metabolism)
• Capillary Permeability (physiology)
• Caspase 3 (metabolism)
• Cell Survival
• Diabetes Mellitus, Experimental (metabolism, pathology)
• Diabetic Retinopathy (metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Fluorescent Antibody Technique, Indirect
• Gene Silencing (physiology)
• Genotype
• In Situ Nick-End Labeling
• Leukostasis (prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Retinal Neurons (pathology)
• Retinal Vessels (pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (physiology)