TISSUE-SPECIFIC AND DIFFERENTIAL REGULATION OF AT₁ AND AT₂ GENE EXPRESSION FOLLOWING ADMINISTRATION OF AN AT₁ ANTAGONIST DURING FETAL LIFE. † 2186

Fetal kidney AT₂ mRNA levels are elevated early in gestation and decrease with fetal maturation, whereas AT₁ mRNA expression increases rapidly before birth. The present study was designed to determine if the developmental rise in AT₁ expression contributes to the decrease in AT₂ expression with advancing gestational age. To test this hypothesis, eight pairs of chronically-instrumented twin fetal sheep (111±2 d gestation, term 145 d) were studied; one of the fetuses received an intravenous infusion of the AT₁ antagonist losartan (L) (20μg/kg/min for 48 h) while the other served as a saline-treated control (C)(0.9% NaCl at 0.1 ml/h). Mean arterial blood pressure did not change in C, but decreased from 40±1 to 33±2 mmHg in L-treated fetuses(p<0.01). Heart rate did not change in C or L fetuses. Plasma renin activity increased significantly (p<0.01) in L-treated fetuses from 4.3±1.3 to 10.7±3.8 ng AI/ml/h. L produced significant(p<0.05) decreases in kidney medulla AT₁ (-32.4±12.6%) and AT₂ mRNA levels (-7.4±2.9%) but did not affect AT₁ or AT₂ expression in the kidney cortex. In the adrenal, L did not alter AT₁ but increased AT₂ expression by 246±130% (p<0.05). L did not alter AT₁ or AT₂ expression in fetal liver. The present results demonstrate that inhibition of AT₁ receptor activity produces tissue-specific and differential regulation of both AT₁ and AT₂ genes during fetal life, and that the decrease in kidney AT₂ expression during fetal development is not dependent on a rise in AT₁ receptor activity.