Role of advanced glycation end-products (AGE) in late diabetic complications

Sensi, M.; Pricci, Flavia; Pugliese, Giuseppe; Rossi, Maria Grazia; Petrucci, Antonio; Cristina, A.; Morano, Susanna; Pozzessere, G.; Valle, E.; Andreani, D; Mario, U. Di

doi:10.1016/0168-8227(94)01061-4

Cited by 62 publications

(37 citation statements)

References 30 publications

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“…However, the extent of ECM and TGF-␤1 mRNA upregulation in our study was lower than that detected in aged rats and closer to that previously observed in diabetic and AGE-injected mice (42,23). The age-dependent increase in RAGE and AGE-R3/galectin-3 and reduction in OST-48/ AGE-R1 transcript level is also consistent with previous reports in aging animals and humans (33,43,48), as the progressive increment in circulating and renal tissue AGEs (46,45), thus supporting the concept that changes in AGE receptor expression are modulated by AGE levels. However, changes in AGE receptors with age were much less pronounced than those of AGE levels, in keeping with the absence of large age-related variations in mRNA expression in rat kidneys (40).…”

Section: Discussionsupporting

confidence: 80%

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

Iacobini¹,

Oddi²,

Menini³

et al. 2005

American Journal of Physiology-Renal Physiology

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. Development of agedependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice. Am J Physiol Renal Physiol 289: F611-F621, 2005. First published May 3, 2005 doi:10.1152/ajprenal.00435.2004.-Aging is characterized by renal functional and structural abnormalities resembling those observed in diabetes. These changes have been related to the progressive accumulation of advanced glycation end-products (AGEs) and cumulative oxidative stress occurring in both conditions. We previously reported that galectin-3 ablation is associated with increased susceptibility to diabetes-and AGE-induced glomerulopathy, thus indicating a protective role of galectin-3 as an AGE receptor. To investigate the role of the AGE/AGE receptor pathway in the pathogenesis of age-related renal disease, we evaluated the development of glomerular lesions in aging galectin-3 knockout (KO) vs. wild-type (WT) mice and their relation to the increased AGE levels and oxidative stress characterizing the aging process. KO mice showed significantly more pronounced age-dependent increases in proteinuria, albuminuria, glomerular sclerosis, and glomerular and mesangial areas, starting at 18 mo, as well as renal extracellular matrix mRNA and protein expression, starting at 12 mo vs. agematched WT mice. Circulating and renal AGEs, plasma isoprostane 8-epi-PGF 2␣ levels, glomerular content of the glycoxidation and lipoxidation products N ⑀ -carboxymethyllysine and 4-hydroxy-2-nonenal, and renal nuclear factor-B activity also increased more markedly with age in KO than WT mice. AGE levels correlated significantly with renal functional and structural parameters. These data indicate that aging galectin-3 KO mice develop more pronounced changes in renal function and structure than coeval WT mice, in parallel with a more marked degree of AGE accumulation, oxidative stress, and associated low-grade inflammation, thus supporting the concept that the AGE/AGE receptor pathway is implicated in agerelated renal disease.age-related glomerulopathy; advanced glycation end-products; advanced glycation end-product receptors; oxidative stress AGING IS A COMPLEX PATHOPHYSIOLOGICAL condition in which the function of many organ systems becomes altered, although it is unclear the extent to which these changes are the result of a normal aging process or of the interplay of age with chronic diseases that are more common in older people. Several changes in kidney function and structure have been detected in aged humans (31) and animals (4). The functional hallmark is a progressive decline of glomerular filtration rate, associated with reduced renal plasma flow and ultrafiltration coefficient, and increased filtration fraction and renal vascular resistance (19,31). From a morphological point of view, the glomerular number is reduced (36), and there is an increased prevalence of global glomerulosclerosis and tubulointerstitial fibrosis, preceded and accompanied by glomerular hypertrophy, mesangial matrix expansion, glomerular basement membrane thickening, and arteriolar hyal...

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Section: Discussionsupporting

confidence: 80%

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

Iacobini¹,

Oddi²,

Menini³

et al. 2005

American Journal of Physiology-Renal Physiology

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“…While the causes of these changes are multifactor, the accumulation of non-enzymatic crosslinks within the family of advanced glycation end-products (AGEs) is increasingly thought to play a role [2]. Formation of AGEs is both spontaneous and quite slow, affecting only proteins with relatively long half-lives and which contain exposed lysine residues [3][4][5][6]. In these respects, fibrillar collagens are highly susceptible to glycation.…”

Section: Introductionmentioning

confidence: 99%

Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue

et al. 2017

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Concurrent with a progressive loss of regenerative capacity, connective tissue aging is characterized by a progressive accumulation of Advanced Glycation End-products (AGEs). Besides being part of the typical aging process, type II diabetics are particularly affected by AGE accumulation due to abnormally high levels of systemic glucose that increases the glycation rate of long-lived proteins such as collagen. Although AGEs are associated with a wide range of clinical disorders, the mechanisms by which AGEs contribute to connective tissue disease in aging and diabetes are still poorly understood. The present study harnesses advanced multiscale imaging techniques to characterize a widely employed in vitro model of ribose induced collagen aging and further benchmarks these data against experiments on native human tissues from donors of different age. These efforts yield unprecedented insight into the mechanical changes in collagen tissues across hierarchical scales from molecular, to fiber, to tissue-levels. We observed a linear increase in molecular spacing (from 1.45 nm to 1.5 nm) and a decrease in the D-period length (from 67.5 nm to 67.1 nm) in aged tissues, both using the ribose model of in vitro glycation and in native human probes. Multiscale mechanical analysis of in vitro glycated tendons strongly suggests that AGEs reduce tissue viscoelasticity by severely limiting fiber-fiber and fibril-fibril sliding. This study lays an important foundation for interpreting the functional and biological effects of AGEs in collagen connective tissues, by exploiting experimental models of AGEs crosslinking and benchmarking them for the first time against endogenous AGEs in native tissue.

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“…This hypothesis is based on the assumption that hyperglycemia is the major risk factor for proliferative changes in the retina in diabetic microvascular complications, especially in DR, 6,[25][26][27] since the degree and duration of hyperglycemia are related with the development of microvascular complications and because correction of hyperglycemia could delay the development of diabetic complications. [20][21][22][23][24] After an experimental model of diabetes was constructed using cultured RPE cells, the effects on the proliferation and migration of RPE cells were examined in this study. Moreover, changes in the expressions of MMPs and TIMPs affecting the activities of MMPs were investigated at the mRNA level by exposing cultured RPE cells to various concentrations of glucose at varying times to observe changes in RPE cells due to glucose and to determine whether these changes are one of the causes of diabetic complications.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Glucose on the Expression of MMP and TIMP in Cultured Retinal Pigment Epithelial Cells

Lee

Kim

Cho

et al. 2004

Korean J Ophthalmol

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This study evaluated the effects of glucose in human retinal pigment epithelial (RPE) cells to investigate the cause of diabetic retinal complications. Human RPE cells were cultured in media containing 5.5 mM, 11.0 mM, and 16.5 mM D-glucose. The present study performed proliferation and migration assays, and conducted western blotting for the protein expression, as well as RT-PCR for the mRNA expression, of MMP-2 and -9, and TIMP-1 and -2. The results of the western blotting analysis showed that increasing glucose concentration significantly increased the expression of MMP-2 and -9, but significantly decreased the expression of TIMP-1 and -2. Moreover, the RT-PCR results indicated significant increases in the mRNA expression of MMP-2 and -9, as well as of TIMP-1 and -2, by raising glucose concentration. This study provides fundamental data for future research on the mechanism of retinal complication in diabetic patients.

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Role of advanced glycation end-products (AGE) in late diabetic complications

Cited by 62 publications

References 30 publications

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue

The Effects of Glucose on the Expression of MMP and TIMP in Cultured Retinal Pigment Epithelial Cells

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