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01.10.2014 | Article

CD40 promotes the development of early diabetic retinopathy in mice

verfasst von: Jose-Andres C. Portillo, Jennifer A. Greene, Genevieve Okenka, Yanling Miao, Nader Sheibani, Timothy S. Kern, Carlos S. Subauste

Erschienen in: Diabetologia | Ausgabe 10/2014

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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.

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Titel: CD40 promotes the development of early diabetic retinopathy in mice
verfasst von: Jose-Andres C. Portillo
Jennifer A. Greene
Genevieve Okenka
Yanling Miao
Nader Sheibani
Timothy S. Kern
Carlos S. Subauste
Publikationsdatum: 01.10.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 10/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3321-x

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CD40 promotes the development of early diabetic retinopathy in mice