Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy.

Autor: Loukovaara S; Unit of Vitreoretinal Surgery, Department of Ophthalmology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland., Sandholm J; Cell Imaging Core, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland., Aalto K; MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Tykistökatu 6A, 20520, Turku, Finland., Liukkonen J; Department of Ophthalmology, Turku University Hospital, Turku, Finland., Jalkanen S; MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Tykistökatu 6A, 20520, Turku, Finland., Yegutkin GG; MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Tykistökatu 6A, 20520, Turku, Finland. gennady.yegutkin@utu.fi.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2017 Feb; Vol. 95 (2), pp. 193-204. Date of Electronic Publication: 2016 Sep 16.
DOI: 10.1007/s00109-016-1472-6
Abstrakt: Clear signaling roles for ATP and adenosine have been established in all tissues, including the eye. The magnitude of signaling responses is governed by networks of enzymes; however, little is known about the regulatory mechanisms of purinergic signaling in the eye. By employing thin-layer chromatographic assays with 3 H-labeled substrates, this study aimed to evaluate the role of nucleotide homeostasis in the pathogenesis of vitreoretinal diseases in humans. We have identified soluble enzymes ecto-5'-nucleotidase/CD73, adenylate kinase-1, and nucleoside diphosphate kinase in the vitreous fluid that control active cycling between pro-inflammatory ATP and anti-inflammatory adenosine. Strikingly, patients with proliferative form of diabetic retinopathy (DR) had higher adenylate kinase activity and ATP concentration, when compared to non-proliferative DR eyes and non-diabetic controls operated for rhegmatogenous retinal detachment, macular hole, and pucker. The non-parametric correlation analysis revealed positive correlations between intravitreal adenylate kinase and concentrations of ATP, ADP, and other angiogenic (angiopoietins-1 and -2), profibrotic (transforming growth factor-β1), and proteolytic (matrix metalloproteinase-9) factors but not erythropoietin and VEGF. Immunohistochemical staining of postmortem human retina additionally revealed selective expression of ecto-5'-nucleotidase/CD73 on the rod-and-cone-containing photoreceptor cells. Collectively, these findings provide novel insights into the regulatory mechanisms that influence purinergic signaling in diseased eye and open up new possibilities in the development of enzyme-targeted therapeutic approaches for prevention and treatment of DR.
Key Message: Ecto-5'-nucleotidase/CD73 and adenylate kinase-1 circulate in human vitreous fluid. Adenylate kinase activity is high in diabetic eyes with proliferative retinopathy. Diabetic eyes display higher intravitreal ATP/ADP ratio than non-diabetic controls. Soluble adenylate kinase maintains resynthesis of inflammatory ATP in diabetic eyes.
Databáze: MEDLINE
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