Heparan sulfate proteoglycans in experimental models of diabetes: a role for perlecan in diabetes complications

Abstract

Proteoglycans are ubiquitous extracellular proteins that serve a variety of functions throughout the organism. Unlike other glycoproteins, proteoglycans are classified based on the structure of the glycosaminoglycan carbohydrate chains, not the core proteins. Perlecan, a member of the heparan sulfate proteoglycan (HSPG) family, has been implicated in many complications of diabetes. Decreased levels of perlecan have been observed in the kidney and in other organs, both in patients with diabetes and in animal models. Perlecan has an important role in the maintenance of the glomerular filtration barrier. Decreased perlecan in the glomerular basement membrane has a central role in the development of diabetic albuminuria. The involvement of this proteoglycan in diabetic complications and the possible mechanisms underlying such a role have been addressed using a variety of models. Due to the importance of nephropathy among diabetic patients most of the studies conducted so far relate to diabetes effects on perlecan in different types of kidney cells. The various diabetic models used have provided information on some of the mechanisms underlying perlecan's role in diabetes as well as on possible factors affecting its regulation. However, many other aspects of perlecan metabolism still await full elucidation. The present review provides a description of the models that have been used to study HSPG and in particular perlecan metabolism in diabetes and some of the factors that have been found to be important in the regulation of perlecan.

Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing

“…Analogously, desulfation triggered by insulin via Sulf2 may induce functional changes in adipocytes. Interestingly, reduced amounts and an altered function of HSPG have been extensively reported in patients with type 2 and also type 1 diabetes [34,35]. The decrease of HSPG and their sulfation in diabetes may be due to a decrease of N-deacetylase [36], possibly induced by a high glucose level [37].…”

Glomerular Endothelial Glycocalyx Constitutes a Barrier to Protein Permeability

“…This could also account for the loss of anionic charge (as a contributor to the onset of albuminuria) reported in conditions such as diabetes, 36 in which both generalized endothelial dysfunction and loss of perlecan in the GBM (perhaps also in glycocalyx) are early features. 36,37 Expression of HS GAG by CiGEnC suggests their potential of regulating interactions with the neighboring cells via the extracellular matrix. The method used to disrupt the glycocalyx using enzymes was based on two specific aims: First, in the case of neuraminidase, to remove the majority of the glycocalyx without disturbing the integrity of the cell monolayer, and, second, with heparinase III and recombinant HPSE-1, to degrade a specific constituent of glycocalyx (HS GAG, implicated in renal pathology).…”

Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice

“…In diabetic nephropathy, studies have suggested that decreased synthesis of heparan sulphate proteoglycans [27][28][29][30] such as perlecan [31] is the reason for altered barrier function. Perlecan and agrin are the major proteoglycans in the GBM, both carrying heparan sulphate.…”