Microvascular basement membranes in diabetes mellitus

Abstract

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.

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

“…The accumulation of AGEs in both the peripheral nerves of human diabetic patients and in the experimental diabetic animals was observed in vascular endothelial cells, pericytes, and the basement membrane, as well as in axons and Schwann cells, thus resulting in an impaired nerve function and characteristic pathological alterations [24,25]. Several lines of evidences suggest that AGEs induce basement-membrane thickening in diabetic nephropathy and retinopathy [13,26]. However, the molecular mechanism underlying this process is unclear in diabetic neuropathy.…”

The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition

“…Expansion of the mesangial layer due to sedimentation of protein in glomerular mesangial space, in the company of partial proliferation [31] plays a significant role in reduction of filtration via decreasing the surface area due to pressing of capillaries [32], or occlusion of capillaries [23]. The elevated level of AGEs in serum also enhances the level of transforming growth factor-b, which in turn stimulates the formation of collagen matrix, or at least in part, basal membrane thickening [30].…”

Vascular growth factor binding kinetics to the endothelial cell basement membrane, with a kinetics-based correction for substrate binding

“…Of particular interest is diabetes, which is marked by dysregulated angiogenesis throughout varied vascular beds. Advanced glycation end products increase both extracellular matrix and growth factor expression, perhaps contributing to the enhanced tissue VEGF observed in diabetic nephropathy and retinopathy (Di Mario and Pugliese 2001;Tsilibary 2003). In diabetic wounds, the precise cellular growth factor response required for efficient healing is disrupted either by altered growth factor concentrations or by unresponsive cells (Falanga 2005).…”