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Differential accumulation of advanced glycation end products in the course of diabetic retinopathy |
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| Authors: | H.-P. Hammes A. Alt T. Niwa J. T. Clausen R. G. Bretzel M. Brownlee E. D. Schleicher |
| Affiliation: | Justus-Liebig-Universit?t Giessen, Giessen, Germany, DE Nagoya University, Daiko Medical Centre, Nagoya, Japan, JP Bio Sciences, Novo Nordisk A/L, Bagsvaerd, Denmark, DK Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA, US Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, Tübingen, Germany, DE |
| Abstract: | Aims/hypothesis. Glycated proteins, formed by reaction of glucose and protein, react further yielding numerous, mostly undefined advanced glycation end products (AGE). The recently characterized imidazolone-type AGE (AG-1) is non-oxidatively formed involving 3-deoxyglucosone whereas some AGEs, particularly Nɛ-(carboxymethyl)lysine (CML), are formed only in the presence of oxygen. Methods. To study the possible contribution of oxidative and non-oxidative AGE formation in the development of diabetic retinopathy antibodies directed against CML-type and imidazolone-type AGEs were characterized by dot blot analysis and used to localize these well-characterized epitops in the retinas from diabetic rats (early course) and from human Type I (insulin-dependent) diabetes mellitus with laser-treated proliferative diabetic retinopathy (late course). Results. In non-diabetic rats CML was moderately positive in neuroglial and vascular structures of non-diabetic rat retinas and increased strongly in diabetic retinas. Anti-imidiazolone antibody staining was strongly positive only in diabetic capillaries. Advanced human diabetic retinopathy showed strong CML-immunolabelling of the entire retina whereas control samples showed moderate staining of neuroglial structures only with the polyclonal CML-antibody. Anti-imidiazolone antibody staining was faint in the inner retina of control sections but were strong throughout the entire diabetic retina. Immunolabelling for the AGE-receptor was congruent with a marker of Müller cells. Conclusion/interpretation. Our data indicate that the oxidatively formed CML is present in non-diabetic retinas as a regular constituent but increases in diabetes both in neuroglial and vascular components. Imidazolone-type AGE are restricted to microvessels and spread during later stages over the entire retina, co-localizing with the expression of AGE-receptor. [Diabetologia (1999) 42: 728–736] Received: 22 October 1998 and in revised form: 11 January 1999 |
| Keywords: | Advanced glycation end products carboxymethyllysine retinopathy extracellular matrix oxidative stress. |
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