Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes.
OBJECTIVE
The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.


METHODS
Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.


RESULTS
All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.


CONCLUSIONS
Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.
Dong
Y F
YF
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
Liu
L
L
Kataoka
K
K
Nakamura
T
T
Fukuda
M
M
Tokutomi
Y
Y
Nako
H
H
Ogawa
H
H
Kim-Mitsuyama
S
S
D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000473:pathology; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D005650:Fumarates / Q000627:therapeutic use*; D018149:Glucose Intolerance / Q000150:complications / Q000473:pathology; D006830:Hydralazine / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009765:Obesity / Q000517:prevention & control*; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000473:pathology*; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D006830:Hydralazine; D000092502:Renin Inhibitors; C446481:aliskiren