Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway

Thallas‐Bonke, Vicki; Lindschau, Carsten; Rizkalla, Bishoy; Bach, Leon Ashley; Boner, G; Meier, Matthias; Haller, Hermann; Cooper, Mark E.; Forbes, Josephine M.

doi:10.2337/diabetes.53.11.2921

Cited by 140 publications

(106 citation statements)

References 49 publications

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“…In fact, nephroprotective agents often reduce proteinuria and AGE accumulation at the same time. However, the specific pathogenetic role of AGEs has been established in animals fed a high vs low AGE diet [37], and pharmacologically using a specific AGE crosslink breaker or AGE inhibitors [32,38,39]. Therefore, although we cannot prove directly the causal link between reduced AGE content and proteinuria in the present study, it seems that the reduction of tissue AGEs, e.g.…”

Section: Discussionmentioning

confidence: 66%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg −1 ·day −1 ), AVE7688 (45 mg·kg −1 ·day −1 ) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes.

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Section: Discussionmentioning

confidence: 66%

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Wihler¹,

Schäfer²,

Schmid³

et al. 2005

Diabetologia

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“…Certainly, alagebrium was able to reduce the accumulation of circulating methylglyoxal and albumin fluorescence, a biomarker of AGE modification [16]. However, other vasculoprotective actions have also been attributed to alagebrium, including inhibition of RAGE-dependent protein kinase C signalling [17] and antioxidant actions. In our study, delayed intervention with alagebrium was associated with a significant attenuation of oxidative stress in the vascular wall, as measured by accumulation of nitrotyrosine residues.…”

Section: Discussionmentioning

confidence: 99%

Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice

et al. 2010

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Aims/hypothesis Formation of AGEs is increased in the diabetic milieu, which contributes to accelerated atherogenesis. We studied whether delayed treatment with AGE-inhibiting compounds, alagebrium chloride and pyridoxamine dihydrochloride, affected established atherosclerosis in experimental diabetes in comparison with the angiotensin-converting enzyme inhibitor, quinapril. Methods Streptozotocin-induced diabetic male Apoe −/− mice (n=24 per group) received, by oral gavage, from week 10 to 20 of diabetes: no treatment; alagebrium (1 mg kg −1 day −1 ); pyridoxamine (1 g/l in drinking water); or quinapril (30 mg kg −1 day −1 ). Atherosclerotic lesion area (en face analysis) was evaluated for all groups. Results Delayed intervention with alagebrium decreased plaque area in the diabetic Apoe −/− mice compared with untreated mice (total plaque area: alagebrium 10.6±1.6%, untreated, 15.1±1.5%, p<0.05). This anti-atherosclerotic effect was comparable with that achieved with quinapril (quinapril 8.4±1.4%, vs untreated, p<0.05). Pyridoxamine also attenuated plaque development in diabetic mice (5.7± 1.2% vs untreated 11.9 ± 1.1%, p < 0.05). The antiatherosclerotic effect conferred by alagebrium and quinapril was associated with a significant reduction in vascular oxidative stress and circulating AGEs and methylglyoxal, although preformed AGEs were not removed from the vascular wall with either delayed intervention. Conclusions/interpretation Inhibition of AGE accumulation, using a delayed intervention with alagebrium or pyridoxamine, significantly attenuated the progression of established diabetes-associated atherosclerosis, similar to results obtained with quinapril. These findings provide further evidence that blockade of AGE-mediated pathways may present a novel therapy for the prevention of atherosclerosis in diabetes.

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“…After transfer, all incubations were conducted on a rocking platform at room temperature. The membrane was blocked in 5% skim milk/TBST overnight, then incubated forreported study that explored the utility of the AGE inhibitor alagebrium chloride on diabetic renal disease (29). In brief, 8-wk-old Sprague-Dawley rats were randomized for the induction of diabetes, via a single injection of the ␤ cell toxin streptozotocin with citrate buffer injection serving as a control.…”

mentioning

confidence: 99%

Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product–Induced Tubular Epithelial-to-Mesenchymal Transition

Burns¹,

Twigg²,

Forbes³

et al. 2006

Journal of the American Society of Nephrology

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Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-␤1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of ␣-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-␤1 antibodies, suggesting that this action was TGF-␤1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 M) or TGF-␤1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-␤1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-␤1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.

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Attenuation of Extracellular Matrix Accumulation in Diabetic Nephropathy by the Advanced Glycation End Product Cross-Link Breaker ALT-711 via a Protein Kinase C-α−Dependent Pathway

Cited by 140 publications

References 49 publications

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice

Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product–Induced Tubular Epithelial-to-Mesenchymal Transition

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