The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

Watson, Anna; Li, J.; Schumacher, Courtney; Gasparo, Marc de; Feng, Biao; Thomas, Merlin C.; Allen, Terri J.; Cooper, Mark E.; Jandeleit‐Dahm, Karin

doi:10.1007/s00125-009-1540-3

Cited by 77 publications

(74 citation statements)

References 42 publications

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“…To this end, we examined the renoprotective effects of orally administrated atrasentan, a selective ET A receptor blocker (16), in a diabetic nephropathy model using apolipoprotein E knockout (apoE KO) mice. This model combines renal and vascular injury with both hyperglycemia and hyperlipidemia, thus mimicking features of diabetic nephropathy (17,18); moreover, it has been shown that the model can be used for pharmacological intervention studies, including studies of ET blockers (17). In this study we show that atrasentan improves endothelial function and results in almost complete restoration of the endothelial glycocalyx while it concomitantly reduces albuminuria.…”

Section: Atrasentan Reduces Albuminuria By Restoring the Glomerular Ementioning

confidence: 59%

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

et al. 2016

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Atrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-tocreatinine ratios by 26.0 6 6.5% (P < 0.01) in apoE knockout (KO) mice with streptozotocin-induced diabetes consuming an atherogenic diet, without changes in gross glomerular morphology, systemic blood pressure, and blood glucose concentration. Endothelial cationic ferritin surface coverage, investigated using large-scale digital transmission electron microscopy, revealed that atrasentan treatment increases glycocalyx coverage in diabetic apoE KO mice from 40.7 6 3.2% to 81.0 6 12.5% (P < 0.05). This restoration is accompanied by increased renal nitric oxide concentrations, reduced expression of glomerular heparanase, and a marked shift in the balance of M1 and M2 glomerular macrophages. In vitro experiments with endothelial cells exposed to laminar flow and cocultured with pericytes confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point toward a role for the restoration of endothelial function and tissue homeostasis through the antialbuminuric effects of atrasentan, and they provide a mechanistic explanation for the clinical observations of reduced albuminuria with atrasentan in diabetic nephropathy.End-stage renal disease is inevitable in a majority of patients with diabetic nephropathy (1), despite optimal blood pressure treatment using drugs that interfere with the reninangiotensin system. Therefore there is a great need for additional strategies to slow the progression of chronic kidney disease in patients with diabetic nephropathy. One such strategy involves interaction with the endothelin (ET) system. Numerous studies involving experimental animal models have implicated ET in the pathogenesis of diabetic nephropathy (2). Moreover, clinical studies show promise for ET receptor antagonists in the treatment of diabetic nephropathy (3-6). This is particularly true for selective ET A receptor blockers; ET A receptor signaling seems to be involved in key renal pathophysiological processes such as the inflammatory response of renal epithelium to albumin (7), whereas stimulation of the associated concomitant ET B receptor can restore endothelial dysfunction by inducing endothelial nitric oxide (NO) production (8-10). Because actual loss of renal function is a late indicator of disease, albuminuria has been put forward as a sensitive surrogate marker for ongoing renal injury in diabetic nephropathy. In this respect ET A receptor blockers seem to have a striking

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Section: Atrasentan Reduces Albuminuria By Restoring the Glomerular Ementioning

confidence: 59%

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

et al. 2016

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“…C, non-diabetic control mice; D, diabetic mice; D ALT, diabetic mice with delayed intervention with alagebrium, 1 mg/kg; D Quin, diabetic mice with delayed intervention with quinapril, 30 mg/kg this delayed therapy, previously our group have demonstrated that blood pressure reduction alone is not sufficient to account for the reduction of diabetes-associated atherosclerosis in this model [21]. Previously, we have found that this dose of quinapril reduced aortic atherosclerosis and nitrotyrosine staining in the diabetic Apoe −/− when used as a preventive (20 week) therapy [12]. The current study found that delayed intervention therapy with quinapril also decreased aortic nitrotyrosine levels.…”

Section: Discussionmentioning

confidence: 94%

“…The current study investigated the effect of a delayed intervention strategy using two separate anti-AGE compounds, alagebrium and pyridoxamine, in a model where diabetes-associated atherosclerosis was already established. We also investigated the effects of the ACE inhibitor, quinapril, which has been shown to have anti-atherosclerotic effects when given as a preventive therapy in this animal model [12].…”

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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“…En face analysis of the percentage of aortic intimal area covered by sudan IV stained atherosclerotic plaque was conducted as described previously [19].…”

Section: Aortic Plaque Areamentioning

confidence: 99%

“…Staining was conducted on paraffin-embedded sections as described previously [19] or as outlined in ESM (Detailed methods) using the primary antibodies listed in ESM Table 1.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

et al. 2013

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Aims/hypothesis The small, highly conserved vasoactive peptide urotensin II (UII) is upregulated in atherosclerosis. However, its effects in diabetes-associated atherosclerosis have not been assessed. Methods Endothelial cells were grown in normal-and highglucose (5 and 25 mmol/l) media with and without UII (10 −8 mol/l) and/or the UII receptor antagonist, SB-657510 (10 −8 mol/l). Apoe knockout (KO) mice with or without streptozotocin-induced diabetes were treated with or without SB-657510 (30 mgkg −1 day −1 ; n=20 per group) and followed for 20 weeks. Carotid endarterectomy specimens from diabetic and non-diabetic humans were also evaluated. Results In high (but not normal) glucose medium, UII significantly increased CCL2 (encodes macrophage chemoattractant protein 1 [MCP-1]) gene expression (human aortic endothelial cells) and increased monocyte adhesion (HUVECs). UII receptor antagonism in diabetic Apoe KO mice significantly attenuated diabetes-associated atherosclerosis and aortic staining for MCP-1, F4/80 (macrophage marker), cyclooxygenase-2, nitrotyrosine and UII. UII staining was significantly increased in carotid endarterectomies from diabetic compared with non-diabetic individuals, as was staining for MCP-1. Conclusions/interpretation This is the first report to demonstrate that UII is increased in diabetes-associated atherosclerosis in humans and rodents. Diabetes-associated plaque development was attenuated by UII receptor antagonism in the experimental setting. Thus UII may represent a novel therapeutic target in the treatment of diabetes-associated atherosclerosis.

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The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

Cited by 77 publications

References 42 publications

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

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

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

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