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The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E
A M D Watson1, J Li, C Schumacher
1Baker IDI Heart and Diabetes Institute, Melbourne, 8008 VIC, Australia. Anna.Watson@bakeridi.edu.au
Aims/Hypothesis:
There is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. This study aimed to assess the effects of the non-peptidergic endothelin receptor A (ETA) antagonist avosentan in a mouse model of accelerated diabetic nephropathy and atherosclerosis in comparison with the ACE inhibitor, quinapril.
Methods:
Apolipoprotein E (Apoe) knockout (KO) mice (n = 20 per group, five groups) were randomised to the following groups: non-diabetic controls and streptozotocin-induced diabetic animals gavaged daily for 20 weeks with placebo, avosentan (high dose: 30 mg/kg, or low dose: 10 mg/kg) or quinapril (given in drinking water, 30 mg/kg).
Results:
BP was unchanged by avosentan treatment but decreased with quinapril treatment. Diabetes-associated albuminuria was significantly attenuated by high-dose avosentan after 10 and 20 weeks of treatment. Diabetic animals showed a decreased creatinine clearance, which was normalised by avosentan treatment. In diabetic mice, high-dose avosentan treatment significantly attenuated the glomerulosclerosis index, mesangial matrix accumulation, glomerular accumulation of the matrix proteins collagen IV, and renal expression of genes encoding connective tissue growth factor, vascular endothelial growth factor, transforming growth factor beta and nuclear factor kappaB (p65 subunit). Furthermore, high-dose avosentan treatment was also associated with reduced expression of the genes for ETA, ETB and angiotensin receptor 1. The renoprotective effects of avosentan were comparable or superior to those observed with quinapril. High-dose avosentan also significantly attenuated diabetes-associated aortic atherosclerosis in Apoe KO mice and reduced macrophage infiltration and aortic nitrotyrosine expression.
Conclusions/Interpretation:
This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro- and macrovascular complications.
Insights
Avosentan, an endothelin receptor A antagonist, significantly reduced kidney damage and aortic atherosclerosis in diabetic mice. This offers a potential new treatment for diabetic complications.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Pharmacology
Background:
- The endothelin system plays a role in diabetic nephropathy and cardiovascular disease.
- Diabetic complications involve microvascular and macrovascular damage.
Purpose of the Study:
- To evaluate the efficacy of avosentan, an endothelin receptor A (ETA) antagonist, in a mouse model of accelerated diabetic nephropathy and atherosclerosis.
- To compare avosentan's effects with those of quinapril, an ACE inhibitor.
Main Methods:
- Apolipoprotein E (Apoe) knockout mice were induced with diabetes using streptozotocin.
- Mice were treated for 20 weeks with placebo, high-dose avosentan (30 mg/kg), low-dose avosentan (10 mg/kg), or quinapril (30 mg/kg).
Main Results:
- High-dose avosentan significantly reduced albuminuria and normalized creatinine clearance in diabetic mice.
- Avosentan treatment attenuated glomerulosclerosis, mesangial matrix accumulation, and inflammatory gene expression in the kidneys.
- Avosentan also reduced aortic atherosclerosis and macrophage infiltration in diabetic Apoe knockout mice.
- Renoprotective effects of avosentan were comparable or superior to quinapril, with no significant change in blood pressure.
Conclusions:
- Endothelin receptor A (ETA) blockade with avosentan demonstrates potential as a therapeutic strategy for diabetic nephropathy.
- Avosentan may offer a novel treatment approach for both microvascular and macrovascular complications associated with diabetes.
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