Linking Biochemistry to Cell Biology of Diabetic Retinopathy The Unifying Hypothesis

The causal link between diabetes and microvascular complications is chronic hyperglycemia. Large prospective clinical studies in both type 1 and type 2 diabetics have demonstrated a strong relationship between glycemia and diabetic microvascular complications. The link between hyperglycemia and endothelial cell damage in diabetes has been intensively studied during the past 20 years. Biochemically, four independent pathways were investigated and led to the development of pharmacological inhibitors

The Biochemistry Diabetes

Figure 3 Biochemistry of diabetic vascular damage: Mitochondrial overproduction of reactive oxygen species (mt-ROS) induces upregulation of poly(ADP-ribose)polymerase (PARP), which inhibits a central enzyme of glycolysis (GAPDH) with subsequent effects on major pathways of hyperglycemia-induced damage. The initiator of mt-ROS is increased transport of glucose into endothelial cells followed by increased flux through glycolysis and the tricarbon cycle. (From Brownlee, Claude Bernard Lecture 2003, Paris.)

Figure 3 Biochemistry of diabetic vascular damage: Mitochondrial overproduction of reactive oxygen species (mt-ROS) induces upregulation of poly(ADP-ribose)polymerase (PARP), which inhibits a central enzyme of glycolysis (GAPDH) with subsequent effects on major pathways of hyperglycemia-induced damage. The initiator of mt-ROS is increased transport of glucose into endothelial cells followed by increased flux through glycolysis and the tricarbon cycle. (From Brownlee, Claude Bernard Lecture 2003, Paris.)

(Figure 3): increased polyol pathway flux, increased advanced glycation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Hyperglycemia-driven mitochondrial overproduction of reactive oxygen species has recently been identified as the underlying biochemical abnormality that is not only a common denominator of the four seemingly unrelated pathways, but also a new crystallization point of concepts for the development of antiangiopathy principles in treatment of diabetes. The model is based on the findings that cells which are exposed to a high ambient glucose, such as endothelial cells, have an increased substrate flux through glycolysis and the TCA cycle. The net result is an increased production of superoxide by the mitochondrial electron transport chain. This induces a substantial reduction in the activity of the glyceraldehyde-phosphate dehydrogenase with an upstream accumulation of glycolytic intermediates such as glycer-aldehyde 3-phosphate and fructose 6-phosphate. These metabolites are important initiators of the previously mentioned biochemical pathways, such as the hexosamine pathway (fructose 6-phosphate) or the protein kinase C pathway (glyceraldehyde 3-phosphate). The mechanism responsible for the inhibition of GAPDH involves ROSmediated activation of poly-ADP-ribose polymerase.

Another approach to alleviate diabetic vascular complications is to shift of the increased flux of toxic intermediates into a nontoxic pathway. Activating transketolase by the cofactor vitamin B1 or lipid-soluble prodrugs such as benfo-tiamin has been shown to reduce all major biochemical pathways activated by hyperglycemia, and reduces acellular capillary formation in diabetic rats. Notably, retinal capillaries did not exhibit any change in pericytes by transketolase activation, but the well-documented increase in endothelial cells in areas not affected by acellular capillaries was reduced toward normal. These findings are consistent with the hypothesis that the endothelium modulates the balance between pericyte-recruiting and pericyte-eliminating factors in chronic hyperglycemia, and that the endothelium is the primary therapeutic target in diabetic microangiopathy.

Glossary

Acellular capillaries: Smallest vessels in the eye in which the cells (endothelial cells and pericytes) have been either lost or destroyed by chronic hyperglycemia, and the subsequent biochemical abnormalities.

Diabetic retinopathy: Most prevalent microvascular complication of common types of diabetes mellitus, affecting vascular and neuroglial structures of the retina.

Microaneurysms: Lesion typical, but not pathognomonic, for incipient diabetic retinopathy. Fusiform or saccular in appearance, microa-neurysms tend to cluster around areas of acellular capillaries, suggesting that they are an early aberrant angiogenic process.

Retinal digest preparation: A method to isolate the retinal vasculature by means of enzymes that digest away neuroglial elements; subsequent staining with periodic acid-Schiff base and hematoxylin-eosin provides a selective view on the retinal vasculature.

Bibliography

Allt, G., and Lawrenson, J. G. (2001). Pericytes: Cell biology and pathology. Cells Tissues Organs 169, 1-11. A recent comprehensive overview on the diverse functions of pericytes throughout the vascular system, and their implications. Antonelli-Orlidge, A., Saunders, K. B., Smith, S. R., and D'Amore, P. A. (1989). An activated form of TGF-beta is produced by co-cultures of endothelial cells and pericytes. Proc. Natl. Acad. Sci. USA 86, 4544-4548. A landmark paper that established the inhibitory role of pericytes in endothelial cell proliferation. Benjamin, L. E., Hemo, I., and Keshet, E. (1998). A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591-1598. Brownlee, M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-820. The most recent integrative review on the effect of high glucose on vascular cells, presenting the new "unifying concept."

Carmeliet, P. (2003). Angiogenesis in health and disease. Nat. Med. 9, 653-660.

Drake, C. J., Hungerford, J. E., and Little, C. D. (1998). Morphogenesis of the first blood vessels. Ann. N. Y. Acad. Sci. 857, 155-179. Du, X., Matsumara, T., Edelstein, D., Rosetti, L., Zsengeller, Z., Szabo, C., and Brownlee, M. (2003). Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J. Clin. Invest. 112, 1049-1057. Gerhardt, H., and Betsholtz, C. (2003). Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 17, 1835-1840. A review that provides new insights into the role of pericytes as modulators of angiogenesis. Hammes, H.-P, Du, X., Edelstein, D., Taguchi, T., Matsumara, T., Ju, Q., Lin, J., Bierhaus, A., Nawroth, P., Hannack, D., Neumeier, M., Bergfeld, R., Giardino, I., and Brownlee, M. (2003). Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat. Med. 9, 294-299. Hellström, M., Gerhardt, H., Kalen, M., Li, X., Eriksson, U., Wolburg, H., and Betsholtz, C. (2001). Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543-553.

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Capsule Biography

Dr. Hammes headed the laboratory of experimental retinopathy at the 3rd Medical Dept., University of Giessen, Germany, from 1989 to 2000. In that time, the laboratory focused on the understanding of the biochemical and cellular mechanisms that lead to the development of early diabetic retinopathy. One question important to Dr. Hammes has always been which mechanisms contribute to the early loss of pericytes in the course of the disease. In 2000, he moved to the Medical School Mannheim, 5th Medical Department, University of Heidelberg. His research is funded by the Deutsche Forschungsgemeinschaft, the German Diabetes Foundation, the European Foundation for the Study of Diabetes, and the Juvenile Diabetes Research Foundation.

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