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J. J. Blom, T. J. Giove, M. M. Deshpande, W. D. Eldred; Modulation of the Adrenomedullin Signaling Pathway in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5362.
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Diabetic retinopathy is a leading cause of vision impairment and blindness in adults. Most research has focused on the vascular pathology and its prevention. However, electrophysiological deficits and neurodegeneration occur before these vascular changes and they have a significant impact on vision. The nitric oxide (NO) signaling pathway is integrally involved in visual processing, and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM), can activate calcineurin, a Ca2+ activated phosphotase that dephosphorylates neuronal nitric oxide synthase (nNOS) at Ser 847 to increase its enzyme activity. ADM levels are elevated in eyes of diabetic patients, and therefore may play a role in the pathology of diabetes and diabetic retinopathy. The goal of this research is to examine the role of the ADM signaling pathway in mice with diabetic retinopathy.
PCR, immunocytochemistry, and NO imaging were used to determine the localization and modulation of the components of the ADM signaling pathway in two diabetic models. Retinal cultures incubated three to four days in high glucose (30mM) were used to identify early changes in an isolated system and the five week streptozotocin induced diabetes (STZID) mouse model was used for longer time points.
NO imaging showed a statistically significant increase in NO production in diabetic retinas. However, there were no significant changes in nNOS mRNA levels, and there was a significant decrease in nNOS protein levels. In retinal cultures or five week diabetic mice, there were increases in ADM-like immunoreactivity (LI) and calcineurin-LI, a decrease in phospho-nNOS(p-nNOS)-LI, and an increase in ADM message using real time PCR. When calcineurin was inhibited with FK506 (1 µM) in 3-4 day cultures, there was an increase in p-nNOS-LI in retinas incubated in 30mM glucose.
These results indicated that the ADM/nNOS/NO signaling pathway was present in retina and that it was altered in diabetes. Continued exploration of this pathway will provide information how this signaling pathway can be selectively targeted to reduce the pathological changes in diabetic retinopathy.
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