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CD40 promotes the development of early diabetic retinopathy in mice
Authors:Jose-Andres C. Portillo  Jennifer A. Greene  Genevieve Okenka  Yanling Miao  Nader Sheibani  Timothy S. Kern  Carlos S. Subauste
Affiliation:1. Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
2. Department of Ophthalmology and Visual Science, University of Wisconsin, Madison, WI, USA
3. Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
4. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, USA
5. Veterans Administration Medical Center, Research Service 151, Cleveland, OH, USA
6. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
Abstract:

Aims/hypothesis

Microangiopathy is a leading complication of diabetes that commonly affects the retina. Degenerate capillaries are a central feature of diabetic retinopathy. An inflammatory process has been linked to the development of diabetic retinopathy but its regulation is incompletely understood. Cluster of differentiation (CD) 40 is a member of the TNF receptor superfamily that promotes the development of certain inflammatory disorders. The role of CD40 in diabetic microangiopathy is unknown.

Methods

B6 and Cd40 ?/? mice were administered streptozotocin to induce diabetes. Leucostasis was assessed using fluorescein isothiocyanate-conjugated concanavalin A. Retinal Icam1 and Cd40 mRNA levels were examined using real-time PCR. Protein nitration was assessed by immunohistochemistry. Histopathology was examined in the retinal vasculature. CD40 expression was assessed by flow cytometry and immunohistochemistry. Intercellular adhesion molecule 1 (ICAM-1) and nitric oxide synthase 2 (NOS2) were examined by immunoblot and/or flow cytometry. Nitric oxide production was examined by immunoblot and Griess reaction.

Results

In mouse models of diabetes, Cd40 ?/? mice exhibited reduced retinal leucostasis and did not develop capillary degeneration in comparison with B6 mice. Diabetic Cd40 ?/? mice had diminished ICAM-1 upregulation and decreased protein nitration. Cd40 mRNA levels were increased in the retinas of diabetic B6 mice compared with non-diabetic controls. CD40 expression increased in retinal Müller cells, endothelial cells and microglia of diabetic animals. CD40 stimulation upregulated ICAM-1 in retinal endothelial cells and Müller cells. CD40 ligation upregulated NOS2 and nitric oxide production by Müller cells.

Conclusions/interpretation

CD40-deficient mice were protected from the development of diabetic retinopathy. These mice exhibited diminished inflammatory responses linked to diabetic retinopathy. CD40 stimulation of retinal cells triggered these pro-inflammatory responses.
Keywords:
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