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 hypercholesterolemic (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-old SHC rats. Urinary albumin, blood pressure (BP), glomerular filtration rate (GFR) and renal histology were examined. In the early phase, both agents inhibited proteinuria and tended to inhibit glomerulosclerosis. TCV-116 also inhibited interstitial inflammation. The antiproteinuric effects did not necessarily correlate with the BP-lowering effects. In the late phase, both agents showed equal antiproteinuric and antihypertensive effects. In 5/6NX and WF rats, TCV-116 inhibited tubulointerstitial inflammation/fibrosis, glomerulosclerosis and renal dysfunction, but enalapril had little effect on these parameters. In the SHC rats, TCV-116 inhibited renal tubulointerstitial inflammation and glomerulosclerosis, but enalapril inhibited only glomerulosclerosis. After drug administration, there was a positive correlation between proteinuria and BP, and a negative correlation between the severity of tissue damage and GFR, but not BP. These findings suggest that initial BP-independent tubulointerstitial inflammation may enhance glomerulosclerosis in the late phase, and TCV-116 might prevent the development of glomerulosclerosis through inhibition of angiotensin II-mediated tubulointerstitial damage in these models.
Shibouta
Y
Y
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Chatani
F
F
Ishimura
Y
Y
Sanada
T
T
Ohta
M
M
Inada
Y
Y
Nishikawa
K
K
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology; D004656:Enalapril / Q000627:therapeutic use; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006937:Hypercholesterolemia / Q000235:genetics / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology*; D009395:Nephritis, Interstitial / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D011355:Prodrugs / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D013777:Tetrazoles; D004656:Enalapril; C077793:candesartan cilexetil