ONTOGENIC CHANGES AND REGULATION OF RENAL ANGIOTENSIN-II TYPE-1 RECEPTOR GENE-EXPRESSION DURING FETAL AND NEWBORN LIFE

Factors regulating the expression of the angiotensin II subtype 1 (AT(1)) receptor during fetal life have not been investigated previously. The present study was designed 1) to characterize the ontogeny of AT(1) receptor gene expression in the kidney of fetal and newborn sheep and 2) to determine the influence of both glucocorticoids and renal nerves in modulating AT(1) gene expression during fetal life and during the transition from fetal to newborn life. We first isolated and cloned a PCR product that has 98 and 94% homology with the cDNA encoding the bovine and pig AT(1) receptors, respectively, and 99 and 98% homology with the corresponding deduced protein sequences. Probing with this cDNA, we demonstrated that renal AT(1) mRNA expression did not change significantly during the last trimester of gestation in fetal sheep or immediately after birth but decreased significantly 10 d after birth. We also demonstrated that renal denervation in the fetus had no effect on renal AT(1) gene expression in 24-h-old newborn lambs. On the other hand, we observed in 130-d twin fetuses that a continuous intraperitoneal infusion (1 mL/h) of cortisol (3 mg/h or 6.2 mu mol/h) for 48 h in one of the twins increased the fetal plasma cortisol concentration from 32.0 +/- 7.1 to 1126 +/- 231 nmol/L and produced a significant decrease (p < 0.005) in renal AT(1) gene expression compared with the control twin receiving an intraperitoneal infusion of 0.9% NaCl. In summary, this study demonstrates that renal AT(1) gene expression is elevated during fetal life and decreases after birth. It is also shown that glucocorticoids, but not renal nerves, contribute to the regulation of renal AT(1) gene expression during development.