ANGIOTENSIN-II TYPE-1 RECEPTOR - ROLE IN RENAL GROWTH AND GENE-EXPRESSION DURING NORMAL DEVELOPMENT

To determine whether angiotensin II (ANG II) modulates renal growth and renin and angiotensin type 1 (AT(1)) gene expression via AT(1) during development, weanling rats were given ANG II antagonist losartan (DuP 753) for 3 wk. Body weight (g), kidney weight (g), and kidney weight-to-body weight ratio were lower in losartan-treated rats (162 +/- 7, 1.6 +/- 0.06, and 9.5 +/- 0.1 x 10(-3)) than in control rats (184 +/- 5, 1.8 +/- 0.07, and 10.1 +/- 0.1 x 10(-3); P < 0.05). Renal DNA content (mg/kidney) was lower in losartan-treated (2.4 +/- 0.17) than in control rats (3.3 +/- 0.31; P < 0.05), whereas protein-to-DNA and RNA-to-DNA ratios were similar in losartan-treated and control rats. Renin mRNA levels were sevenfold higher in losartan-treated than in control rats, as determined by quantitative standardized dot blot analysis. In addition, blockade of AT(1) with losartan induced recruitment of renin-synthesizing and renin-containing cells in the renal vasculature, as determined by immunocytochemistry and in situ hybridization. To establish whether AT(1) blockade has a direct effect on renin gene expression, freshly isolated renin-producing cells were exposed in vitro to losartan (10(-6) M) or culture media (control). Losartan induced a twofold increase in steady-state renin mRNA levels above control (P < 0.05). Intrarenal AT(1) mRNA levels were not altered by losartan given either in vivo or in vitro to freshly dispersed cells. To define whether immature renin-secreting cells are responsive to ANG II, renin release was determined by reverse hemolytic plaque assay. The baseline number of renin-releasing cells was higher in newborn (26 +/- 3.1) than in adult rats (13 +/- 1.0; P < 0.05). ANG II (10(-7) M) decreased the number of renin-releasing cells by 39 +/- 5.8% in newborns and 39 +/- 6.8% in adults. We conclude that 1) the AT(1) receptor mediates renal and somatic ANG II-induced growth by regulating cell hyperplasia, 2) ANG II exerts a tonic inhibition on renin gene expression during normal development via AT(1) receptor, 3) newborn renin-secreting cells are responsive to ANG II, and 4) AT(1) gene is not regulated by receptor binding in the developing kidney.