TCV-116 and enalapril were given in two stages: (early phase) for 6 to
10 weeks to 5/6 nephrectomized (NX) rats two weeks after nephrectomy,
12-week-old Wistar fatty (WF) rats and 7 week-old spontaneously hyper
cholesterolemic (SHC) rats; and (late phase) for 6 to 16 weeks to 5/6
NX rats 11 weeks after nephrectomy, 27-week-old WF rats and 10-week-ol
d SHC rats. Urinary albumin, blood pressure (BP), glomerular filtratio
n rate (GFR) and renal histology were examined. In the early phase, bo
th agents inhibited proteinuria and tended to inhibit glomeruloscleros
is. TCV-116 also inhibited interstitial inflammation. The antiproteinu
ric effects did not necessarily correlate with the BP-lowering effects
. In the late phase, both agents showed equal antiproteinuric and anti
hypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubuloin
terstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunc
tion, but enalapril had little effect on these parameters. In the SHC
rats, TCV-116 inhibited renal tubulointerstitial inflammation and glom
erulosclerosis, but enalapril inhibited only glomerulosclerosis. After
drug administration, there was a positive correlation between protein
uria and BP, and a negative correlation between the severity of tissue
damage and GFR, but not BP. These findings suggest that initial BP-in
dependent tubulointerstitial inflammation may enhance glomeruloscleros
is in the late phase, and TCV-116 might prevent the development of glo
merulosclerosis through inhibition of angiotensin II-mediated tubuloin
terstitial damage in these models.