Differential gene expression and regulation of renal angiotensin II receptor subtypes (AT1 and AT2) during fetal life in sheep.

Previous studies have shown that angiotensin II subtype 2 (AT2) receptors appear early during renal embryonic development. Factors involved in the regulation of AT2 receptors during renal development, however, have not been investigated. The present study was designed 1) to characterize the ontogeny of renal AT2 gene expression during the last half of gestation in fetal sheep and newborn lambs, 2) to compare changes in AT1 and AT2 gene expression during renal development, 3) to determine the influence of AII in modulating renal AT1 and AT2 gene expression during fetal life, and 4) to characterize the role of cortisol in modulating renal AT2 gene expression during the last trimester of gestation in fetal sheep. To perform these studies, we first isolated and cloned a polymerase chain reaction product that has 92 and 90% homology with the cDNA encoding the human and rat AT2 receptors, respectively. Using this sheep AT2 cDNA probe, we demonstrated that the sheep AT2 gene was encoded in a single locus. In addition, we showed that renal AT2 mRNA expression was high early during fetal life (60-90-d gestation) and decreased rapidly thereafter. In contrast, the expression of renal AT1 receptor gene was low at 60-d gestation and increased during the last trimester of gestation. We found that a continuous i.v. infusion (1 mL/h) of AII (9.5 mM/n) for 24 h, which raised plasma AII levels from 84 +/- 9 pg/mL to 210 +/- 21 pg/mL, decreased the expression of both renal AT1 and AT2 genes in third trimester fetal sheep. On the other hand, we observed that cortisol, known to decrease AT1 gene expression in the fetus, had no effect on AT2 gene expression. In summary, this study demonstrates that AII, but not glucocorticoids, contributes to the regulation of renal AT2 gene expression during development and that there is differential regulation of AT1 and AT2 receptors.