Effects of candesartan, an angiotensin II type 1 receptor blocker, on diabetic nephropathy in KK/Ta mice.
BACKGROUND
Although therapeutic effects of angiotensin II type 1 receptor blocker (ARB) on renal injury in non-insulin dependant diabetes mellitus (NIDDM) have been demonstrated, the beneficial effects and their mechanisms in diabetic nephropathy have not been well evaluated.


METHODS
KK/Ta mice were divided into three groups according to the treatment: candesartan 4 mg/kg/day from 6 to 28 weeks of age (group I; early treatment); from 12 to 28 weeks of age (group II; late treatment); only vehicle (group III). BALB/c mice treated with vehicle were used as controls (group IV). Body weight (BW), systolic blood pressure (SBP), blood glucose, urinary type IV collagen and albumin excretion were measured every 4 weeks. Morphometry and immunohistology of albumin, transforming growth factor-beta1 (TGF-beta1) and Smad7 were performed in all groups.


RESULTS
BW and blood glucose were higher in groups I, II and III than in group IV from 8 weeks. SBP was markedly reduced in groups I and II compared with group III (p < 0.05, p < 0.005). Urinary type IV collagen and albumin excretion were increased in group III compared to group IV (p < 0.05, p < 0.005), whereas they were reduced in groups I and II when compared to group III (p < 0.05). Morphometric analysis revealed that the whole glomerular area (WGA), glomerular tuft area (GTA), extracellular matrix area (ECMA) and intraglomerular cell nuclei number (NIGCN) were significantly reduced in groups I, II and IV compared to group III at 28 weeks. In immunohistochemistry, TGF-beta1 expression in both glomeruli and tubules of groups I and II decreased compared to that of group III at 28 weeks, while Smad7 in group III glomeruli was reduced compared to that in groups I and II.


CONCLUSIONS
It appears that candesartan reduced urinary type IV collagen and albumin excretion, and attenuated glomerular hypertrophy and mesangial matrix accumulation by the TGF-betaS/Smad signaling pathway in KK/Ta mice with diabetic nephropathy.
Liao
Jie
J
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Kobayashi
Michimasa
M
Kanamuru
Yutaka
Y
Nakamura
Shinji
S
Makita
Yuichiro
Y
Funabiki
Kazuhiko
K
Horikoshi
Satoshi
S
Tomino
Yasuhiko
Y
D000419:Albuminuria; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D024141:Collagen Type IV / Q000652:urine; D003404:Creatinine / Q000097:blood; D004268:DNA-Binding Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000473:pathology; D005920:Glomerular Mesangium / Q000473:pathology; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D015398:Signal Transduction; D051906:Smad7 Protein; D013777:Tetrazoles / Q000627:therapeutic use*; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D001786:Blood Glucose; D024141:Collagen Type IV; D004268:DNA-Binding Proteins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D013777:Tetrazoles; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003404:Creatinine; C081643:candesartan