The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice.
OBJECTIVE
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
This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro- and macrovascular complications.
Baker IDI Heart and Diabetes Institute, Melbourne, 8008 VIC, Australia. Anna.Watson@bakeridi.edu.au
A M D
AM
Watson
J
J
Li
C
C
Schumacher
M
M
de Gasparo
B
B
Feng
M C
MC
Thomas
T J
TJ
Allen
M E
ME
Cooper
K A M
KA
Jandeleit-Dahm
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D006943:Hyperglycemia / Q000235:genetics; D006949:Hyperlipidemias / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D000077583:Quinapril; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use
D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D044005:Tetrahydroisoquinolines; C484919:Avosentan; D000077583:Quinapril