Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes

The short- and long-term effects of specific angiotensin II (All) receptor blockade on the evolution of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the All receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal 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. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the All receptor antagonist. The results presented here strongly indicate that reduction of All activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of All activity.