CD40 promotes the development of early diabetic retinopathy in mice
- Resource Type
- Authors
- Timothy S. Kern; Nader Sheibani; Yanling Miao; Jose-Andres C. Portillo; Carlos S. Subauste; Jennifer A. Greene; Genevieve Okenka
- Source
- Diabetologia. 57(10)
- Subject
- Male
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Ependymoglial Cells
Inflammation
Real-Time Polymerase Chain Reaction
Article
Pathogenesis
Mice
Internal medicine
Diabetes mellitus
Internal Medicine
medicine
Animals
Retina
CD40
Diabetic Retinopathy
Cluster of differentiation
biology
business.industry
Microangiopathy
Endothelial Cells
Diabetic retinopathy
medicine.disease
Flow Cytometry
Immunohistochemistry
Endocrinology
medicine.anatomical_structure
Immunology
biology.protein
medicine.symptom
business
Microtubule-Associated Proteins
- Language
- ISSN
- 1432-0428
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.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.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.CD40-deficient mice were protected fromthe development of diabetic retinopathy. These mice exhibited diminished inflammatory responses linked to diabetic retinopathy. CD40 stimulation of retinal cells triggered these pro-inflammatory responses.