Effect of candesartan cilexetil (TCV-116) in rats with chronic renal failure.
BACKGROUND
Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats.


METHODS
Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria.


RESULTS
In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not.


CONCLUSIONS
These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.
Noda
M
M
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Noda_Masakuni@takeda.co.jp
Matsuo
T
T
Fukuda
R
R
Ohta
M
M
Nagano
H
H
Shibouta
Y
Y
Naka
T
T
Nishikawa
K
K
Imura
Y
Y
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000378:metabolism; D015232:Dinoprostone / Q000652:urine; D004195:Disease Models, Animal; D004656:Enalapril / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D004656:Enalapril; D003404:Creatinine; D012083:Renin; D015232:Dinoprostone; C077793:candesartan cilexetil