Characterization of the nitric oxide and adrenomedullin signaling pathways in normal and diabetic mouse retina
Embargo Date
Indefinite
OA Version
Citation
Abstract
Nitric oxide (NO), a gaseous neuromodulator, has physiological functions in every cell type in the retina. NO often functions through the second messenger cyclic guanosine monophosphate (cGMP). Immunocytochemistry was used to localize and characterize the NO/cGMP signaling pathway in specific regions and cell types within the mouse retina. The NO signaling pathway is activated in eyes of diabetic patients and NO imaging shows increased NO production in diabetic mouse retinas. In contrast, there are no significant changes in neuronal nitric oxide synthase (nNOS) mRNA levels, and nNOS protein is decreased. The signaling peptide adrenomedullin (ADM) can activate calcineurin, a Ca2+ activated phosphatase that dephosphorylates nNOS at Se~47 to increase its enzyme activity. ADM levels are elevated in eyes of diabetic patients, and therefore ADM may play a role in the pathology of diabetic retinopathy. The results in this thesis and are the first to show that ADM, and it's receptors were present and functional in the mouse retina. Inhibition of this pathway decreased NO production in high glucose retinal cultures. Treating diabetic mice with the PKC 13 inhibitor ruboxistaurin for 5 weeks lowered ADM mANA levels and ADM-Iike immunoreactivity, and preserved retinal function as assessed by electroretinography. The results of this thesis indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.
Description
Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.