Aliskiren enhances protective effects of valsartan against type 2 diabetic nephropathy in mice.
OBJECTIVE
Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy.


METHODS
db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group.


RESULTS
Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy.


CONCLUSIONS
Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.
Dong
Yi-Fei
YF
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Liu
Lei
L
Lai
Zhong-Fang
ZF
Yamamoto
Eiichiro
E
Kataoka
Keiichiro
K
Nakamura
Taishi
T
Fukuda
Masaya
M
Tokutomi
Yoshiko
Y
Nako
Hisato
H
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000419:Albuminuria / Q000150:complications / Q000378:metabolism; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D024141:Collagen Type IV / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*; D004357:Drug Synergism; D005650:Fumarates / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D000577:Amides; D024141:Collagen Type IV; D005650:Fumarates; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; C446481:aliskiren; D000068756:Valsartan; D014633:Valine; D019808:Losartan