Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.
Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.
Fan
Yu-Yan
YY
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Baba
Ryoko
R
Nagai
Yukiko
Y
Miyatake
Akira
A
Hosomi
Naohisa
N
Kimura
Shoji
S
Sun
Guang-Ping
GP
Kohno
Masakazu
M
Fujita
Mamoru
M
Abe
Youichi
Y
Nishiyama
Akira
A
D000450:Aldosterone / Q000502:physiology*; D000804:Angiotensin II / Q000097:blood / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003401:Creatine / Q000097:blood; D006973:Hypertension / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009392:Nephrectomy; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D012965:Sodium Chloride; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; C526316:CCN2 protein, rat; D007093:Imidazoles; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D012965:Sodium Chloride; D000450:Aldosterone; C437965:olmesartan; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D003401:Creatine