Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor.

Abstract

Renal disease is one of the most common and severe complications of diabetes mellitus. The hallmark of the disease, glomerulosclerosis, is characterized by an accumulation of extracellular matrix in the mesangial areas, leading to progressive obliteration of the vascular spaces. The role of the metabolic derangements of diabetes mellitus in the development of these lesions is incompletely understood. One of the consequences of hyperglycemia is the formation of advanced glycosylation end products (AGEs), which result from a series of rearrangements secondary to nonenzymatic reaction of glucose with proteins. Specific receptors for proteins modified by AGEs, present in several cell types, were recently described in human and rat mesangial cells. Furthermore, exposure of mesangial cells to AGEs was followed by an increase in fibronectin production. In the present study we show evidence that mouse mesangial cells exhibit an increase in collagen type IV mRNA and peptide synthesis after exposure to AGEs. Antibodies to AGE receptors prevent this increase, indicating that the response is AGE-receptor-mediated. In addition, anti-platelet-derived growth factor abrogates the AGE response, suggesting that platelet-derived growth factor acts as an intermediate factor. Transcription assay reveals that the elevated mRNA levels are due to an increase in the transcription rate, rather than to an increase in the stability of the message. Finally, the mRNAs coding for laminin and heparan sulfate proteoglycan are also increased after exposure to AGE, whereas glyceraldehyde 3-phosphate dehydrogenase mRNA levels remain constant. The increase in extracellular matrix mRNAs seen in the current study suggests that AGE formation in vivo may be one of the metabolic events leading to the development of diabetic glomerulosclerosis.

Toxic action of advanced glycation end products on cultured retinal capillary pericytes and endothelial cells: relevance to diabetic retinopathy

“…As expected [9] cell surface binding of radiolabelled AGE-BSA by aortic endothelial cells is followed by receptor-mediated endocytosis and the accumulation of the material inside the cells. In contrast to previous reports we failed to observe the release of any degradation products into the media over the 24-h incubation.…”

“…The binding of AGEmodified proteins with RAGE has been shown to mediate monocyte migration and activation [31], induce oxidative stress on endothelial cells [34], and increase the expression of the vascular cell adhesion molecule-1 (VCAM-1) [35]. The binding of AGE to the p60 and p90 component of the AGE-receptors on mesangial cells can also induce the synthesis of basement membrane collagen IV, laminin and heparan sulphate proteoglycan [9]. This upregulation of collagen IV by AGE appears to be mediated by platelet derived growth factor (PDGF) since the AGE-mediated effect could be blocked by the addition of PDGF antibody [9].…”

“…AGE modification of mesangial cell matrix has been reported to alter the mesangial proliferative response [8]. The addition of AGE-modified proteins to cultures of mouse mesangial cells results in the increased synthesis and production of extracellular matrix components, such as fibronectin and collagen [9]. AGE-modified proteins bind specifically to AGE-receptors on the surface of endothelial cells, resulting in receptor-mediated endocytosis, changes in cellular proliferation, endothelial cell permeability, coagulant functions [10] and altered expression of endothelialderived relaxing activity [11].…”

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…Their importance as mediators of renal injury has been amply demonstrated by studies using inhibitors of AGE formation [13][14][15] or dietary restriction of AGEs [16] to retard nephropathy without influencing glycaemic control. In addition, in vivo exposure of healthy adult animals to AGEs is able to generate glomerular lesions similar to those seen in diabetes, in the absence of hyperglycaemia [7,17].…”

Renal clearance of glycolaldehyde- and methylglyoxal-modified proteins in mice is mediated by mesangial cells through a class A scavenger receptor (SR-A)

“…Second, AGE proteins prepared by the modification of BSA with ribose, induced TGF-β synthesis at an mRNA level in rat mesangial cells [10]. Third, AGE proteins prepared by incubating BSA with glucose-6-phosphate increased the levels of growth factors such as TGF-β and IGF-I and extracellular matrix proteins such as fibronectin, laminin and type IV collagen at the protein level in rat mesangial cells [11,12]. Fourth, AGE proteins prepared by incubating BSA with glucose-6-phosphate also increased type IV collagen expression in human mesangial cells [13].…”