Hormones – Cytokines – Signalling
Kidney International (1999) 56, 898–909; doi:10.1046/j.1523-1755.1999.00614.x
Effect of candesartan cilexetil (TCV-116) in rats with chronic renal failure
Masakuni Noda, Takanori Matsuo, Ryo Fukuda, Masayuki Ohta, Hiroko Nagano, Yumiko Shibouta, Takehiko Naka, Kohei Nishikawa and Yoshimi Imura
Pharmaceutical Research Laboratories II, Drug Safety Research Laboratories, and Research Management Department, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
Correspondence: Masakuni Noda, Ph.D., Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85 Juso-Honmachi, Yodogawa-ku, Osaka 532-8686, Japan. E-mail: Noda_Masakuni@takeda.co.jp
Received 16 June 1998; Revised 15 April 1999; Accepted 24 April 1999.
Abstract
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-
1 (TGF-1) 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-1, and interstitial fibrosis, whereas enalapril did not.
Conclusion
These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.
Keywords:
renoprotection, angiotensin II receptor antagonist, nephrectomy, progressive renal disease, injury, ACE inhibitor
Abbreviations:
ACEIs, angiotensin I-converting enzyme inhibitors; Ang II, angiotensin II; AT1A, angiotensin II type 1 receptor antagonist; BK, bradykinin; CCr, creatinine clearance; BUN, blood urea nitrogen; EDTA, ethylenediaminetetraacetic acid; H&E, hematoxylin and eosin; 5/6 NX rats, 5/6 nephrectomized rats; PAM, periodic acid-methenamine silver; PGE2, prostaglandin E2; PRA, plasma renin activity; RAS, renin-angiotensin system
