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  • Title: Role of β-adrenergic receptor regulation of TNF-α and insulin signaling in retinal Muller cells.
    Author: Walker RJ, Anderson NM, Jiang Y, Bahouth S, Steinle JJ.
    Journal: Invest Ophthalmol Vis Sci; 2011 Dec 16; 52(13):9527-33. PubMed ID: 22110065.
    Abstract:
    PURPOSE: The goal of this study was to determine the relationship of TNF-α and the downregulation of insulin receptor signaling in retinal Müller cells cultured under hyperglycemic conditions and the role of β-adrenergic receptors in regulating these responses. METHODS: Retinal Müller cells were cultured in normal (5 mM) or high (25 mM) glucose until 80% confluent and then were reduced to 2% serum for 18 to 24 hours. The cells were then treated with 10 μM salmeterol followed by Western blot analysis or ELISA. For TNF-α inhibitory studies, the cells were treated with 5 ng/mL of TNF-α for 30 minutes or by a 30-minute pretreatment with TNF-α followed by salmeterol for 6 hours. In the TNF-α short hairpin (sh)RNA experiments, the cells were cultured until 90% confluent, followed by transfection with TNF-α shRNA for 18 hours. RESULTS: TNF-α-only treatments of Müller cells resulted in significant decreases of tyrosine phosphorylation of the insulin receptor and Akt in high-glucose conditions. Salmeterol (10 μM), a β-2-adrenergic receptor agonist, significantly increased phosphorylation of both insulin receptor and Akt. TNF-α shRNA significantly decreased phosphorylation of IRS-1(Ser307), which was further decreased after salmeterol+TNF-α shRNA. Both TNF-α shRNA and salmeterol significantly reduced death of the retinal Müller cells. CONCLUSIONS: These studies demonstrate that β-adrenergic receptor agonists in vitro can restore the loss of insulin receptor activity noted in diabetes. By decreasing the levels of TNF-α and decreasing the phosphorylation of IRS-1(Ser307) while increasing tyrosine phosphorylation of insulin receptor, these results suggest a possible mechanism by which restoration of β-adrenergic receptor signaling may protect the retina against diabetes-induced damage.
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