GAG abnormalities in diabetic nephropathy were originally investigated on the bases that albuminuria implies abnormal GBM permselectivity, and that GAGs, namely HS, were thought to be important determinants of GBM permeability. Indeed, a decreased 35S sulfate incorporation in the GBM of diabetic glomeruli has been observed [14-16]. In experimental animal models of diabetes, a reduced synthesis of glomerular PGs and basement membrane HS-PG was also found [17-19]. However, the finding of the reduced sulfate incorporation is not without controversy, and a marked increase in 35S sulfate incorporation in proteoglycans in diabetic tissues has also been observed . Studies using biochemical techniques to measure the GAG content of kidneys obtained at autopsy demonstrated that the GBM of patients with diabetic nephropathy (it was not specified whether type 1 or type 2 diabetes) contained less GAGs than kidneys of non-diabetic controls [21,22]. That the synthesis of carbohydrate side chains of HS-PGs can be altered in type 1 diabetes mellitus was also shown by a ultrastructural investigation by Vernier et al  who described a negative correlation between GBM HS-PG deposition and mesangial expansion in diabetic nephropathy.
This was confirmed by a study using of JM-403, a monoclonal antibody that reacts with HS-GAG side chains, mainly staining the GBM in normal kidneys: in a mixed group of type 1 and type 2 patients with diabetic nephropathy it showed a decreased intensity of GBM staining correlated with proteinuria . In the same subjects no statistically significant change in HS-PG core protein staining was observed. The effects of the diabetic milieu on glomerular HS-PG synthesis have been studied in vitro by different groups using glomerular cell cultures . When human podocytes and mesangial cells were cultured under high glucose conditions, and stained with the monoclonal antibody JM-403, a decreased staining in the extracellular matrix was observed . By metabolic labeling an altered GAG production under high glucose conditions was shown, with predominantly a decrease in HS, compared with dermatan or chondroitin sulfate .
A study carried out using two different antibodies raised against different epitopes of the HS-GAG side chain has shown a decreased HS N sulfation of urinary GAGs in type 2 diabetic patients possibly pointing to a reduced sulfation of HS within the GBM in diabetic patients . However, whether the patients with diabetic nephropathy had a more severe disturbance was not evident from that study since normoalbuminuric patients and patients with incipient nephropathy had similar urinary levels of N sulfated HS.
The first major GBM HS-PG to be identified was perlecan ; this molecule is also a normal constituent of the basement membrane of vessels . Therefore, it was an appealing candidate as a target for the deranged metabolism of diabetes in micro- and macroangiopathy and for explaining the reduced HS synthesis in diabetes mellitus and namely in diabetic nephropathy. However, immunohistochemistry with antibodies against perlecan HS-PG core proteins did not reveal any significant change in diabetic nephropathy in IDDM patients [7,29].
Thus, taken together the above mentioned findings suggested a vulnerability in the metabolism of the negatively charged side chain of HS-PG in diabetic nephropathy rather than a decreased synthesis of the whole HS-PG.
Nevertheless perlecan has a glomerular localization that does not resemble the distribution of HS-PG using antibodies directed against HS-PG isolated from the GBM [30-32]. Indeed, two other HS-PG core proteins have been identified in the GBM: agrin  and collagen XVIII . Agrin, which has been demonstrated to be present only in the kidney , the retina  and the nervous system , seems to be the major HS-PG present in the GBM ; thus, it is reasonable to hypothesize that agrin contributes to the GBM charge permselectivity and, by interacting with laminin, to the GBM architecture. Yard et al  have recently discovered a reduction in both the agrin (core protein) and JM-403 (HS side chains) staining in renal biopsies from type 2 diabetic patients. Furthermore, a reduction in the agrin synthesis by podocytes in high glucose cultures was also revealed . These recent findings in type 2 diabetic patients with diabetic nephropathy challenge the idea that a selective dysregulation of HS-PG sulfation occurs, rather than a reduction in the synthesis of HS-PG as a whole molecule.
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