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Robert Jason Walker
Beta-2-Adrenergic Receptor Regulates Insulin Signaling to Reduce Cell Death in Müller Cells
Integrated Program in Biomedical Sciences
Track, if Integrated Program in Biomedical
beta-adrenergic receptors, diabetes, Muller cells, retina
Changes in the diabetic retina likely occur in response to a variety of insults, including high glucose, oxidative stress, and increased levels of inflammatory markers. Müller cells become activated and express increased glial fibrillary acidic protein levels in diabetes. This suggests that these cells are in a reactive state that may alter their regulation of inflammatory markers, glucose transport, oxidative stress, growth factors, and cell survival. During the onset of diabetes, there is a loss of sympathetic nerve activity that takes place in different regions of the body. Previous studies from our lab suggested that loss of sympathetic neurotransmission induces diabetic-like changes to the retina, specifically in Müller cells and endothelial cells. In previous studies, we found that retinal Müller cells possess beta-1 and beta-2 adrenergic receptors, and with those findings we used a non-specific beta agonist, isoproterenol as a treatment to stimulate both receptors. In addition we used a selective beta-2-adrenergic receptor agonist, salmeterol, to selectively stimulate the beta-2-adrenergic receptor in Müller cells. Salmeterol significantly increased tyrosine phosphorylation of the insulin receptor, Akt, and significantly reduced apoptosis in retinal Müller cells. Our data showed that salmeterol reduced TNF-α levels. TNF-α phosphorylates IRS-1 on Ser307 and inhibits insulin signaling. Salmeterol inhibited , TNF-α and thereby increased insulin signal transduction. Based upon these findings, we generated shRNA against TNF-α and IRS-1. Knockdown of IRS-1 with shRNA significantly increased in cell death compared to retinal Müller cell samples cultured in 5mM glucose alone. However stimulation of beta-2-adrenergic receptor prevented cell death through IRS-1 in a hyperglycemic environment. We demonstrated that knockdown of TNF-α by shRNA significantly reduced the phosphorylation of serine 307 on IRS-1, leading to increased Akt activity. Our results are in agreement with other studies in adipose cells, that found TNF-α to be a negative regulator of the insulin receptor signaling. We believe that these results provide a putative mechanism for the effects of beta-adrenergic receptors in reducing retinal damage in diabetes. These studies will help to further characterize the function of beta-2-adrenergic receptors in the retina and also in a disease state, such as diabetic retinopathy.
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