Nilvadipine attenuates mesangial expansion and glomerular hypertrophy in diabetic db/db mice, a model for type 2 diabetes.
BACKGROUND
The renoprotection achieved by angiotensin II blockade in the treatment of diabetic nephropathy is well established in both the clinical and the experimental settings. In contrast, the therapeutic efficacy of calcium channel blockers (CCBs) in the treatment of diabetic nephropathy still remains controversial.


METHODS
In the present study, we compared the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a dihydropyridine CCB, nilvadipine, on nephropathy in the db/db mouse, a rodent model of type 2 diabetes. Male db/db mice were divided into the following three groups at the age of 11 weeks, when treatment was started: vehicle, enalapril (10 mg/kg per day), and nilvadipine (10 mg/kg per day). Blood pressure, urine, and blood chemistry were monitored at the age of 17 and 27 weeks, and kidney samples were obtained at 29 weeks. Morphological changes were analyzed on periodic acid-Schiff-stained sections. Lipid peroxidation in kidney homogenates was measured.


RESULTS
Blood pressure remained normal and was similar in the three groups until 27 weeks. Blood glucose exceeded 300 mg/dl throughout the study in all groups. Reduction of microalbuminuria at 27 weeks, compared to the vehicle group, was 37% and 52% in the enalapril- and nilvadipine-treated groups, respectively. Increased lipid peroxidation was suppressed by 15% and 83% in the enalapril- and nilvadipine-treated groups, respectively. Glomerular hypertrophy, assessed by cross-sectional glomerular area, was significantly suppressed in the nilvadipine group, but not in the enalapril group, compared to the vehicle group.


CONCLUSIONS
Nilvadipine shows a stronger renoprotective effect than enalapril in the db/db mouse, independent of the blood-pressure-lowering effect. An antioxidative effect, indicated by the reduction in lipid peroxidation, may partly contribute to the renoprotection conferred by nilvadipine.
Second Department of Medical Science, School of Health and Sport Sciences, Osaka University, 1-17 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan. moriyama@wellness.hss.osaka-u.ac.jp.
Toshiki
T
Moriyama
Kazumasa
K
Oka
Hirotsugu
H
Ueda
Enyu
E
Imai
D000419:Albuminuria; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000502:physiology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology*; D004656:Enalapril / Q000627:therapeutic use; D005920:Glomerular Mesangium / Q000473:pathology*; D006984:Hypertrophy; D007677:Kidney Function Tests; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D002121:Calcium Channel Blockers; C035100:nilvadipine; D008315:Malondialdehyde; D004656:Enalapril; D009543:Nifedipine