Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease.

Abstract

Several lines of evidence suggest that the excessive accumulation of extracellular matrix in the glomeruli of diabetic kidneys may be due to reactive intermediates forming between glucose and matrix proteins called advanced glycation end products (AGEs). Normal mice received AGEmodified mouse serum albumin i.p. for 4 weeks, and glomerular extracellular matrix, growth factor mRNA levels, and morphology were examined. We found that AGE induced an increase in glomerular extraceflular matrix al(IV) collagen, laminin Bi, and transforming growth factor Pis mRNA levels, as measured by competitive PCR, as well as glomerular hypertrophy. The AGE response was specific because the coadministration of an AGE inhibitor, aminoguanidine, reduced all these changes. We conclude that AGEs affected expression of genes implicated in diabetic kidney disease and may play a major role in nephropathy.reactive AGEs, thus preventing AGE-protein cross-linking (14). Among other effects, nG was shown to reduce AGE content of aortic tissue in long-term-diabetic rats (15) and attenuate the glomerular lesions in diabetic rats (16), suggesting that AGEs participate in the development of these lesions. When the response(s) of cultured renal mesangial cells to AGE-albumin was examined, we found that the in vitro expression and secretion of several ECM components were up-regulated through surface receptors (17, 18). Furthermore, normal rats chronically injected with AGE developed vascular dysfunction and glomerular lesions (19,20), which were markedly reduced in those cotreated with nG.

Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy

“…Plasma or serum levels of C-reactive protein (CRP) were measured by immunonephelometry (IMMAGE Nephelometer, Beckman Coulter). TNF␣ mRNA levels in mononuclear cells were measured by RT-PCR as described (31), and TNF␣ protein and VCAM-1 were measured by ELISA kits (BioSource International, Camarillo, CA and R & D Systems). sAGE levels were measured by CML-sensitive ELISA (4G9) (24,25).…”

Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury

“…The mechanisms by which AGE binding to its receptor may lead to the pathological features of diabetic complications have begun to be explored. For instance, administration of AGE proteins to normal mice results in upregulation of the prosclerotic cytokine transforming growth factor (TGF)b in glomeruli, possibly mediating the increase in extracellular matrix gene expression and glomerular hypertrophy observed in this model [46]. In vitro studies by Doi et al [47] have suggested that platelet derived growth factor (PDGF) may also mediate the increase in extracellular matrix production by mesangial cells on exposure to AGE proteins.…”

Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

“…Neutralizing anti-TGF-b antibodies in vivo suppressed diabetes-related kidney growth [49]. In vivo studies have shown treatment with AGE-modified mouse serum albumin, generated in vitro, induced gene expression of type IV collagen and TGF-b1 in the glomeruli [15]. Intensive investigation into the pathogenesis of ECM accumulation in diabetes has consistently implicated the prosclerotic cytokine, TGF-b, as a key mediator [21,22].…”

“…Aminoguanidine (AG) [23], a hydrazine-like compound which blocks AGE formation by interacting with Amadori-derived products [24], has been shown to retard the development of diabetic microvascular and macrovascular complications in experimental animals [10,12,13,15,25,26]. In relation to diabetic nephropathy, AG attenuates the rise in albuminuria and prevents mesangial expansion in diabetic rats [27,28].…”