SHORT-TERM AND LONG-TERM EFFECT OF ANGIOTENSIN-II RECEPTOR BLOCKADE IN RATS WITH EXPERIMENTAL DIABETES

The short- and long-term effects of specific angiotensin II (AII) rece ptor blockade on the evolution of glomerular injury in moderately hype rglycemic diabetic rats were studied. Three groups of animals were use d, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor a ntagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than norma l controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Di abetic animals had higher urinary protein excretion and glomeruloscler osis incidence than did normal controls. Losartan significantly preven ted proteinuria and glomerulosclerosis. Evaluation of the sieving prop erties of the glomerular membrane by Ficoll fractional clearance showe d an important increase in the filtration of this marker in diabetic a nimals, as compared with that in controls, and almost complete prevent ion of this change in losartan-treated animals. Theoretical analysis o f fractional clearance data with a heteroporous model of glomerular si ze-selectivity showed that in diabetic animals the size of membrane po res was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activit y plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed w ith angiotensin-converting enzyme inhibition in this model depend dire ctly on the reduction of AII activity.