Fetal ontogeny and role of metanephric bradykinin B-2 receptors

Previous studies in rats have shown that blockade of bradykinin B-2 recepto rs (B2R) in combination with a high-salt intake during gestation result in poor postnatal survival and long-term hypertension in the offspring. In thi s study, we examined the fetal ontogeny of B2R and determined the consequen ces of gestational B2R blockade and high salt on kidney development. B2R ge ne expression is induced on embryonic day (E16) of fetal metanephrogenesis and remains sustained until term. The earliest expression of the B2R protei n is observed on apical membranes of ureteric bud branches and in capillary loop stage glomeruli. By the end of gestation, B2R becomes restricted to m ore-differentiated tubules in the deep cortex and medulla. Pairs of rats on normal (0.12 mmol/g) or high (0.84 mmol/g) salt diets were mated at 14 wee ks of age. The B2R antagonist, Icatibant (previously known as Hoe-140) (300 nmol/kg per day) or saline (vehicle) was infused intraperitoneally during gestation via osmotic minipumps. Fetuses were examined on E20 (n=27-36 per group. No significant differences in litter size or body weight were observ ed among the groups. Combined high-salt and Icatibant treatment caused aber rant fetal renal development characterized by tubular dysgenesis, widened s tromal mesenchyme, and glomerular cysts. The dysgenetic tubules stained pos itively for the distal nephron lectin, Dolichos biflorus, and exhibited enh anced Bar expression and apoptosis. Renal microvascular development, the nu mber of mature glomeruli, and percentage of proliferating glomerular cells were not affected. Gestational Icatibant or high salt alone had no deleteri ous effects on fetal nephrogenesis. We conclude that gestational blockade o f the kallikrein-kinin system impairs fetal nephrogenesis if combined with an intrauterine stressor such as high-salt intake. B2R may play a protectiv e role during segmental nephron differentiation.