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 (AT(1)As) and angiotensin I-converting enzym e inhibitors (ACEIs) shows renoprotective effects in rats with chronic rena l failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexet il (TCV-116), an AT(1)A, and enalapril, an ACEI, in the progressive phase o f renal injury in 5/6 nephrectomized rats. Methods. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) w ere orally administered once a day for 3 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 mar ked proteinuria. Results. In vehicle-treated rats, proteinuria, glomerulosclerosis, and inte rstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta(1) (TGF-beta(1)) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experimen t, both drugs inhibited them. In the long-term experiment? the progressive proteinuria and the elevation of blood pressure were similarly attenuated b y both drugs. However, candesartan cilexetil significantly inhibited the pr ogression of glomerulosclerosis, the expression of TGF-beta(1), and interst itial fibrosis, whereas enalapril did not. Conclusion. These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously deve loped renal injury.