Candesartan reduced advanced glycation end-products accumulation and diminished nitro-oxidative stress in type 2 diabetic KK/Ta mice.
BACKGROUND
Angiotensin-II induces nitro-oxidative stress in patients with diabetic nephropathy. Peroxynitrite and reactive oxide species can accelerate formation of advanced glycation end-products (AGEs). We investigated the effects of candesartan, an angiotensin-II type 1 receptor blocker (ARB), on the formation of AGEs and nitro-oxidative stress in type 2 diabetic KK/Ta mouse kidneys.


METHODS
KK/Ta mice were divided into three treatment groups: an early treatment group receiving 4 mg/kg/day candesartan from 6 to 28 weeks of age, a late treatment group receiving the same candesartan dose from 12 to 28 weeks of age and a group receiving the vehicle for candesartan. BALB/c mice treated with vehicle were used as controls. We evaluated at 28 weeks the renal expressions of carboxymethyllysine, the receptor for AGE (RAGE), the p47phox component of NADPH oxidase, endothelial nitric oxide synthase (eNOS), induced nitric oxide synthase (iNOS) and 8-OHdG and nitrotyrosine by immunohistochemistry and/or by competitive RT-PCR.


RESULTS
Kidneys from KK/Ta mice showed increased formation of AGEs, nitro-oxidative stress and RAGE expression and these were attenuated by candesartan treatment. Protein and mRNA expressions of p47phox and iNOS were upregulated in KK/Ta kidneys, which also showed increased immunostaining intensities of 8-OHdG and nitrotyrosine. Treatment with candesartan attenuated all of these changes and prevented significant albuminuria. There were no significant differences in the expression of eNOS among the four groups.


CONCLUSIONS
These findings suggest that candesartan, an ARB, reduces AGE accumulation and subsequent albuminuria by down-regulating the NADPH oxidase p47phox component and iNOS expression and by attenuating RAGE expression in type 2 diabetic KK/Ta mouse kidneys.
Fan
Qiuling
Q
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Liao
Jie
J
Kobayashi
Michimasa
M
Yamashita
Michifumi
M
Gu
Leyi
L
Gohda
Tomohito
T
Suzuki
Yusuke
Y
Wang
Li Ning
LN
Horikoshi
Satoshi
S
Tomino
Yasuhiko
Y
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D017931:DNA Primers; D017127:Glycation End Products, Advanced; D013777:Tetrazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C081643:candesartan