Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse.
OBJECTIVE
To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.


METHODS
The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks.


RESULTS
Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways.


CONCLUSIONS
Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.
Chew
Phyllis
P
Oxidative Stress Laboratory, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Yuen
Derek Y C
DY
Stefanovic
Nada
N
Pete
Josefa
J
Coughlan
Melinda T
MT
Jandeleit-Dahm
Karin A
KA
Thomas
Merlin C
MC
Rosenfeldt
Franklin
F
Cooper
Mark E
ME
de Haan
Judy B
JB
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000517:prevention & control*; D001393:Azoles / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005979:Glutathione Peroxidase / Q000172:deficiency*; D054833:Isoindoles; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D000447:Aldehydes; D000975:Antioxidants; D001057:Apolipoproteins E; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C002744:3-nitrotyrosine; C042986:ebselen; D014443:Tyrosine; D005979:Glutathione Peroxidase; C027576:4-hydroxy-2-nonenal; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
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