The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia-induced alteration of the pattern of podocyte-integrin expression, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti-VEGF antibodies attenuates glomerular basement membrane thickening, platelet-derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation endproducts but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified.
Basement membranes contain a number of intrinsic macromolecular components which are unique to these structures and which cooperatively assemble into specific heteropolymeric matrices. Type IV collagen triple helical monomers bind together at their amino-terminal, carboxy-terminal, and lateral domains to form a lattice-like array. Laminin, in a two-step process, binds to itself at its terminal globular domains to form polymers and also binds collagen at two I This work was supported by a Career Development Award from the Juvenile Diabetes Foundation (PDY), Hull Endowment Fund (ECT), NIH training grant GM-07562 (ASC), and NIH grant AM-30556 (HF). 2 Presented in part at the symposium on the BASEMENT MEMBRANE FUNCTION AND MORPHOGENESIS, May 5, 1985, as part of the program at the annual meeting of the Histochemical Society, held in Crystal City,
Abstract. Laminin and type IV collagen were compared for the ability to promote aortic endothelial cell adhesion and directed migration in vitro. Substratumadsorbed IV promoted aortic endothelial cell adhesion in a concentration dependent fashion attaining a maximum level 141-fold greater than controls within 30 min. Aortic endothelial cell adhesion to type IV collagen was not inhibited by high levels (10 -3 M) of arginyl-glycyl-aspartyl-serine. In contrast, adhesion of aortic endothelial cells on laminin was slower, attaining only 53 % of the adhesion observed on type IV collagen by 90 min. Type IV collagen when added to the lower well of a Boyden chamber stimulated the directional migration of aortic endothelial cells in a concentration dependent manner with a maximal response 6.9-fold over control levels, whereas aortic endothelial cells did not migrate in response to laminin at any concentration (.01-2.0 x 10 -7 M). Triple helix-rich fragments of type IV collagen were nearly as active as intact type IV collagen in stimulating both adhesion and migration whereas the carboxy terminal globular domain was less active at promoting adhesion (36% of the adhesion promoted by intact type IV collagen) or migration. Importantly, aortic endothelial cells also migrate to substratum adsorbed gradients of type IV collagen suggesting that the mechanism of migration is haptotactic in nature. These results demonstrate that the aortic endothelial cell adhesion and migration is preferentially promoted by type IV collagen compared with laminin, and has a complex molecular basis which may be important in angiogenesis and large vessel repair.
In cultured human glomerular epithelial cells (HGEC), 25 mM glucose resulted in decreased expression of alpha(3)-, alpha(2)-, and beta(1)-integrins and increased expression of alpha(5)- and alpha(v)beta(3)-integrins. This change was accompanied by decreased binding of HGEC to type IV collagen. In the presence of normal (5 mM) glucose concentration, cell binding to type IV collagen was primarily mediated by alpha(2)beta(1)- and alpha(5)beta(1)-integrins, as indicated by experiments in which cell adhesion to type IV collagen was competed by specific anti-integrin monoclonal antibodies. In the presence of high (25 mM) glucose, the upregulated alpha(5)- and alpha(v)beta(3)-integrins were mainly involved in cell binding to type IV collagen. Furthermore, high glucose decreased expression of matrix metalloproteinase-2 (MMP-2), a collagenase regulated in part by alpha(3)beta(1)-integrin, as suggested by the use of ligand-mimicking antibodies against these integrins, which resulted in release of increased amounts of MMP-2 in the culture medium. Finally, tissue inhibitor of metalloproteinase-2, the specific inhibitor of MMP-2, was upregulated in high glucose and could contribute to matrix accumulation. These changes could help explain basement membrane thickening in diabetes.
A mixture of laminin and type IV collagen was analyzed by rotary shadowing using carbon/platinum and electron microscopy. Laminin was found to form distinct complexes with type IV collagen: one site of interaction is located 140 nm from the COOH-terminal, noncollagenous (NC1) domain and the other is located within the NH2-terminal region. The isolated NC1 fragment of type IV collagen does not appear to interact with laminin, while pepsin-treated type IV collagen, which lacks the NC1 domain, retains its ability to form complexes with laminin. Analysis of the laminin-type IV complexes indicates that laminin binds to type IV collagen via the globular regions of either of its four arms. This finding is supported by experiments using fragment P1 of laminin which lacks the globular regions and which does not bind to type IV collagen in a specific way. In addition, after heat-denaturation of laminin no specific binding is observed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.