SCIENCE WATCH Glycosaminoglycans: Use in Treatment of Diabetic Nephropathy

Because diabetic nephropathy occurs in 20 to 40% of patients with diabetes mellitus, it has become one of the most important causes of end-stage renal disease. The latest incidence figures vary from 16% of patients starting with dialysis in The Netherlands (1) to 42% in the United States (2). Diabetic nephropathy has a large impact in terms of associated morbidity and mortality for the individual patient and in terms of costs for health care (3). The duration and efficacy of treating hyperglycemia (4), as well as BP regulation (5,6) and genetic factors (7–10), are probably all important in the pathogenesis of diabetic nephropathy in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). Several retrospective and prospective studies have demonstrated that microand macroalbuminuria predict cardiovascular morbidity and mortality in diabetes mellitus (reviewed in reference (11). Although Rossing et al. recently reported that the prognosis for patients with overt diabetic nephropathy has improved, 15% of IDDM patients with normoalbuminuria, 25% with microalbuminuria, and 44% with overt nephropathy died during their 10-yr follow-up study (12). How albuminuria and proteinuria are linked with macroangiopathy is poorly understood, and many hypotheses have been formulated and tested. The Steno hypothesis, first advanced by Deckert et al. in 1988, held that a genetic defect in the regulation of heparan sulfate (HS) production by endothelial, myomedial, and mesangial cells determines the susceptibility of diabetic patients to develop proteinuria and angiopathy with its associated cardiovascular risk (13). The sulfation pattern of the glycosaminoglycan (GAG) side chains of HS proteoglycans (HSPG) plays a pivotal role in this hypothesis. The central idea is that diabetic patients susceptible to nephropathy and macroangiopathy have a genetic trait leading to a lower activity of the enzymes responsible for GAG sulfation under high glucose conditions. The resulting undersulfated GAG chains would then play a crucial role in the pathogenesis of proteinuria (due to the loss of anionic charges in the glomerular basement membrane [GBM]) and its morphologic substrate, diabetic nephropathy, as well as in the pathogenesis of diabetic microand macroangiopathy. Although genes have been cloned for N-deacetylase/N-sulfotransferase, 3-O-sulfotransferase, and 6-O-sulfotransferase enzymes (reviewed in reference (14), it is still unclear whether different allotypes of these enzymes with a different susceptibility to high glucose concentrations really exist. Although the Steno hypothesis has not been formally proven, it has stimulated in vitro studies and therapeutic trials in experimental animal models and patients.