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Molecular basis for a link between complement and the vascular complications of diabetes

J Acosta1, J Hettinga, R Flückiger

  • 1Laboratory for Membrane Transport, Harvard Medical School, 240 Longwood Avenue, C1-607, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 11, 2000
PubMed

Insights

In diabetes, glucose damages CD59, a protein that normally prevents cell overgrowth. This damage allows the membrane attack complex (MAC) to stimulate blood vessel growth, contributing to diabetic complications.

Area of Science:

  • Immunology
  • Endocrinology
  • Molecular Biology

Background:

  • The membrane attack complex (MAC) promotes cell proliferation by stimulating growth factor release from endothelial cells.
  • CD59 is a complement regulatory protein that inhibits MAC formation.
  • Diabetic vascular complications are characterized by increased cell proliferation, potentially linked to protein glycation.

Purpose of the Study:

  • To investigate if protein glycation, caused by high glucose levels in diabetes, inhibits the function of CD59.
  • To determine if glycated CD59 leads to increased MAC deposition and subsequent cell proliferation.

Main Methods:

  • In vivo analysis of human CD59 for glycation.
  • Functional assays to assess MAC-inhibitory activity of glycated CD59.
  • Site-directed mutagenesis to identify glycation sites on CD59.

Main Results:

  • Human CD59 is glycated in vivo.
  • Glycation inactivates CD59's ability to inhibit MAC formation.
  • Inactivated CD59 enhances MAC-induced growth factor release from endothelial cells.
  • Residues K41 and H44 were identified as a preferential glycation motif in human CD59.

Conclusions:

  • Glycation of CD59 in diabetes impairs its regulatory function, leading to increased MAC activity.
  • This mechanism contributes to the vascular proliferative complications observed in human diabetes.
  • The specific glycation motif in human CD59 may explain its unique susceptibility to diabetic vascular disease.

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