CS-886, a new angiotensin II type 1 receptor antagonist, ameliorates glomerular anionic site loss and prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rats.
BACKGROUND
Diabetic nephropathy is a leading cause of end-stage renal disease in industrialized countries. Previous studies have documented that angiotensin converting enzyme (ACE) inhibitors consistently reduce albuminuria and retard the progression of diabetic nephropathy. However, the involvement of angiotensin II in diabetic nephropathy is not fully understood.


METHODS
In this study we compared the effects of CS-866, a new angiotensin II type 1 receptor antagonist, to that of an ACE inhibitor, temocapril hydrochloride, on the development and progression of diabetic nephropathy using Otsuka Long-Evans Tokushima fatty rats, a type II diabetes mellitus model animal.


RESULTS
High doses of CS-866 or temocapril treatment were found to significantly improve urinary protein and beta(2)-microglobulin excretions in diabetic rats. In electron microscopic analysis, loss of glomerular anionic sites, one of the causes of glomerular hyperpermeability in diabetic nephropathy, was found to be significantly prevented by CS-866 treatment. Light microscopic examinations revealed that both treatments ameliorated glomerular sclerosis and tubulointerstitial injury in diabetic rats. Furthermore, high doses of CS-866 or temocapril treatment significantly reduced the positive stainings for transforming growth factor-beta (TGF-beta), vascular endothelial growth factor, and type IV collagen in glomeruli of diabetic rats.


CONCLUSIONS
These results indicate that intrarenal angiotensin II type 1 receptor activation plays a dominant role in the development and progression of diabetic nephropathy. Our study suggests that CS-866 represents a valuable new drug for the treatment of diabetic patients with nephropathy.
Koga
Kohachiro
K
Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Yamagishi
Sho-ichi
S
Takeuchi
Masayoshi
M
Inagaki
Yosuke
Y
Amano
Shinjiro
S
Okamoto
Tamami
T
Saga
Tsuyoshi
T
Makita
Zenji
Z
Yoshizuka
Mitsuaki
M
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000838:Anions; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D000068557:Olmesartan Medoxomil; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D020334:Rats, Inbred OLETF; D012720:Severity of Illness Index; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013841:Thiazepines / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D047228:Angiotensin II Type 1 Receptor Blockers; D000838:Anions; D007093:Imidazoles; D013777:Tetrazoles; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D000068557:Olmesartan Medoxomil; C055603:temocapril hydrochloride