DIFFERENTIAL GENE-EXPRESSION AND REGULATION OF RENAL ANGIOTENSIN-II RECEPTOR SUBTYPES (AT(1) AND AT(2)) DURING FETAL LIFE IN SHEEP

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