Potentiation by candesartan of protective effects of pioglitazone against type 2 diabetic cardiovascular and renal complications in obese mice.
OBJECTIVE
The efficacy of renin-angiotensin system (RAS) blockers on type 2 diabetes and its complications remains to be defined. This study was undertaken to test the hypothesis that candesartan may enhance the protective effects of pioglitazone against type 2 diabetes.


METHODS
We compared the effects of pioglitazone, candesartan, and their combination on cardiorenal and vascular injury, diabetes, and tissue oxidative stress in obese and type 2 diabetic db/db mice, and also examined the effects of tempol, a superoxide dismutase (SOD) mimetic, on db/db mice to define the role of oxidative stress.


RESULTS
The addition of candesartan to pioglitazone significantly potentiated the suppressive effects of pioglitazone on cardiac macrophage infiltration and interstitial fibrosis, and glomerular macrophage infiltration and sclerosis in db/db mice. These benefits of the combination of pioglitazone and candesartan in db/db mice were attributed to additive attenuation of cardiorenal oxidative stress, through the attenuation of NADPH oxidase or the restoration of Cu/Zn-SOD and EC-SOD. The combination of these drugs reversed vascular endothelial dysfunction in db/db mice more than either monotherapy, by causing more phosphorylation of eNOS. Candesartan slightly augmented the improvement of glucose tolerance by pioglitazone in db/db mice, and this additive effect was mediated by more attenuation of oxidative stress.


CONCLUSIONS
Our work demonstrated that candesartan significantly potentiated the protective effects of pioglitazone against cardiorenal and vascular injury, and diabetes in obese type 2 diabetic mice. Thus, the combination of pioglitazone with candesartan is potentially a promising therapeutic strategy for type 2 diabetes.
Department of Pharmacology and Molecular Therapeutics, Japan.
Masaya
M
Fukuda
Taishi
T
Nakamura
Keiichiro
K
Kataoka
Hisato
H
Nako
Yoshiko
Y
Tokutomi
Yi-Fei
YF
Dong
Hisao
H
Ogawa
Shokei
S
Kim-Mitsuyama
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003573:Cytochrome b Group / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004357:Drug Synergism; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007668:Kidney / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000188:drug therapy; D018384:Oxidative Stress / Q000187:drug effects; D000077205:Pioglitazone; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage*; D045162:Thiazolidinediones / Q000008:administration & dosage*
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides; D003573:Cytochrome b Group; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D013113:Spin Labels; D013777:Tetrazoles; D045162:Thiazolidinediones; D013482:Superoxide Dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; C081643:candesartan; C001803:tempol; D000077205:Pioglitazone