Pathogenesis of diabetic vascular disease: evidence for the role of reduced heparan sulfate proteoglycan.
Insulin-dependent diabetic patients with increased urinary albumin excretion are characterized by elevated blood pressure and declining kidney function. In addition, such patients have a high risk of atherosclerotic vascular disease, proliferative retinopathy, and cardiomyopathy, suggesting that albuminuria is a marker of widespread vascular dysfunction. Increased transport of macromolecules across the vascular wall, elevated plasma levels of von Willebrand factor, and impaired fibrinolytic capacity have been demonstrated in albuminuric patients. The cause of this vascular vulnerability in susceptible patients is unknown, but increasing evidence has suggested that loss of the proteoglycan heparan sulfate in the vasculature may explain the widespread nature of the disease. Heparan sulfate is important for the glomerular endothelial cell and basement membrane charge densities, the anticoagulant properties of the vessel wall, and the growth regulation of intimal smooth muscle cells. Recent studies have shown that heparin increases the biosynthesis of heparan sulfate in endothelial cell cultures and prevents the characteristic glomerular basement membrane thickening when given to diabetic rats. Moreover, heparin has been shown to reduce albuminuria in patients with incipient diabetic nephropathy. Although increasing evidence supports the hypothesis that loss of heparan sulfate may play a pathophysiological role in the development of diabetic vascular complications, there are still many unresolved problems. What are the mechanisms of action of glycosaminoglycans at the molecular biology level, and how can we select compounds without anticoagulant activity suitable for long-term use in the prevention and treatment of late diabetic complications?
Jensen
T
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Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Denmark.
D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology; D003928:Diabetic Nephropathies / Q000209:etiology*; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000627:therapeutic use*; D006801:Humans; D011509:Proteoglycans / Q000627:therapeutic use*
D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D011509:Proteoglycans