Effects of UP269-6, a new angiotensin II receptor antagonist, and captopril on the progression of rat diabetic nephropathy.
To estimate the effects of UP269-6, a nonpeptide angiotensin II receptor antagonist, and captopril, a converting enzyme inhibitor, on the progression of nephropathy, 77 uninephrectomized diabetic rats were maintained for 8 months with plasma glucose levels from 300 to 500 mg/dL. Systemic and renal parameters were periodically measured, and, at the time of death, a histological evaluation of renal damage was performed. Control rats (no additional treatment but insulin) showed increased blood pressure and urinary albumin levels, together with prominent alterations in the kidney (renal and glomerular hypertrophies, tubular atrophy, and 19% of sclerotic glomeruli). Captopril (50 mg/kg/day) and UP269-6 (10 mg/kg/day) reduced blood pressure and albumin excretion levels, and improved histological renal preservation (lower renal and glomerular hypertrophies, tubular atrophy, and percentage of sclerotic glomeruli: 5% and 7%, respectively). Finally, a low dose of UP269-6 (1 mg/kg/day), which induced an intermediate level of blood pressure between control and the other treated groups, produced an equivalent degree of nephroprotection. Our data demonstrate the efficacy of this new angiotensin II receptor antagonist on the progression of diabetic renal damage. These results also reinforce the role attributed to angiotensin II in the development of renal derangement in this model, as UP269-6 is devoid of agonistic effect on the kinin system.
Villa
E
E
Endocrinology Department, Hospital Ramon y Cajal, Madrid, Spain.
Rábano
A
A
Cazes
M
M
Cloarec
A
A
Ruilope
L M
LM
García-Robles
R
R
D000419:Albuminuria / Q000139:chemically induced / Q000473:pathology; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D007668:Kidney / Q000473:pathology; D009392:Nephrectomy; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D011743:Pyrimidines; D013777:Tetrazoles; D000804:Angiotensin II; C088791:UP 269-6; D002216:Captopril; D003404:Creatinine