TCV-116 INHIBITS RENAL INTERSTITIAL AND GLOMERULAR INJURY IN GLOMERULOSCLEROTIC RATS

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.