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

Abstract

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.