Effect of Diabetes on the Glycosaminoglycan Component of the Human Glomerular Basement Membrane

Abstract

SUMMARYThe glycosaminoglycan (heparan sulfate) component of glomerular basement membranes from human kidneys of diabetic and nondiabetic subjects has been quantitated after isolation from protease digests of the membranes on OEAE-cellulose microcolumns. A significant decrease (P < 0.005) in the glycosaminoglycan content of diabetic membranes was observed. Heparan sulfate was identified as the predominant glycosaminoglycan in both diabetic and control subjects and the extent of its sulfation appeared to be similar. The reduced level of glycosaminoglycan in the diabetic glomerular basement membrane was accompanied by a significant elevation of hexoses, which are primarily associated with the collagen component, suggesting that a redistribution of basement membrane macromolecules occurs in the diabetic state. Since heparan sulfate has been implicated as a major component of the glomerular anionic filtration barrier, its decreased content in diabetic basement membranes may contribute to the proteinuria observed in this disease. DIABETES 37:738-741, August 1982.A lthough it has been recognized for some time that basement membrane thickening and mesangial expansion is a characteristic morphologic feature of diabetic glomerulopathy, the relationship between these ultrastructural alterations and the clinically observed proteinuria remains to be established. 1 As the major functional component of the renal glomerulus and the only continuous anatomic barrier between the blood and urine, the basement membrane would appear to be a logical site at which changes brought about by disease could lead to a filtration defect.The primary factors determining glomerular basement membrane permeability appear to be pore size as well as fixed electrostatic charge.2 While the former may be a function of packing of the collagen polypeptide chains, recent studies suggest that the latter may reside in a heparan sulfate glycosaminoglycan 3 that has been isolated, characterized, and shown to be an integral constituent of the basement membrane. 4>sSince the glycosaminoglycan component was until lately unrecognized and is present in very small amounts 6 ( < 1 % by weight), previous studies of diabetic basement membranes have not provided information on this component.In the present investigation we have quantitated the heparan sulfate of glomerular basement membranes from human diabetics with the help of a recently developed DEAE-cellulose microcolumn fractionation procedure 6 and find that it is present in significantly decreased amounts. MATERIALS AND METHODSHuman kidneys from diabetic and nondiabetic subjects were obtained at autopsy from the New England Deaconess and the Brigham and Women's Hospitals and stored at -70°C in airtight plastic bags until use. Glomerular basement membranes from individual kidneys were studied from 9 diabetic and 10 nondiabetic subjects, whose ages ranged from 43 to 66 yr (mean 60 yr) and from 37 to 68 yr (mean 59 yr), respectively. In both groups all individuals but one were above the age of 50. In the diabetics...

Modulatory effect of bitter gourd (Momordica charantia LINN.) on alterations in kidney heparan sulfate in streptozotocin-induced diabetic rats

“…The content of uronic acid and amino sugar-building blocks of GAG also decreased during diabetes resulting in decreased content of GAG. These results correlated with the studies using kidneys obtained at autopsy to measure GAG content of GBM in patients with diabetic nephropathy, which contained reduced amount of GAG than kidneys of non-diabetic controls (Parthasarathy and Spiro, 1982). Decreased synthesis of glomerular proteoglycans and basement membrane heparan sulfate proteoglycans (HSPG) during diabetes has been reported by many workers in mice and rats (Cohen and Surma, 1981;Kanwar et al, 1983;Rohrbach et al, 1983).…”

Size and Charge Selectivity of the Glomerular Filter in Patients with Insulin-Dependent Diabetes mellitus: Urinary Immunoglobulins and Glycosaminoglycans

“…However, the degree of sulphating of the GAGs is not affected [3]. Thus, the decrease in total sulphated GAG excretion observed in the present study probably reflects a real decrease in amount of GAG.…”

“…In contrast, there is a decrease or redistribution in negatively charged groups of GAGs [1, 2, 3, 4, 5, 28]in the GBM. Hypothetically, as mentioned above, this may lead to albuminuria [7, 13]and increased excretion of IgG4 [8, 9, 10, 11, 12, 13, 28].…”

“…Diabetic nephropathy is associated with a decreased glomerular synthesis of glycosaminoglycans (GAGs) [1, 2, 3, 4, 5, 6]. The latter confer a negative charge to the glomerular basement membrane (GBM) and the glomerular filter as a whole.…”

Effects of advanced glycosylation endproducts on perlecan core protein of glomerular epithelium

“…In studies on human diabetic kidney tissues, the structural or compositional changes found in GBM and podocytes showed increases in the amount of type IV collagen, laminin, and fibronectin, with a simultaneous reduction in the anionic components including HSPG [9]. A relative reduction in heparan sulfate (HS) and HSPG was also observed in the GBM of diabetic patients [10,11,12]. Some authors have noted a decreased staining for HS side chains in the GBM in human diabetic kidneys, with no change in the GBM staining for the core protein of HSPG [4,13].…”