Highly regulated cell type-restricted expression of human renin in mice containing 140-or 160-kilobase pair P1 phage artificial chromosome transgenes

We generated transgenic mice with two P1 artificial chromosomes, each conta ining the human renin (HREN) gene and extending to -35 and -75 kilobase pai rs, respectively. HREN protein production was restricted to juxtaglomerular cells of the kidney, and its expression was tightly regulated by angiotens in II and sodium. The magnitude of the up- and down-regulation in HREN mRNA caused by the stimuli tested was identical to the endogenous renin gene, s uggesting tight physiological regulation. P1 artificial chromosome mice wer e mated with transgenic mice overexpressing human angiotensinogen to determ ine if there was a chronic compensatory down-regulation of the transgene, D espite a 3-fold down-regulation of HREN mRNA, plasma angiotensin II and blo od pressure was modestly elevated in the double transgenic mice. Neverthele ss, this elevation was significantly less than a different double transgeni c model containing a poorly regulated HREN transgene. The increase in blood pressure, despite the decrease in HREN mRNA, suggests that the HREN gene c an partially, but not completely, compensate for excess circulating angiote nsinogen. These data suggest the possibility that increases in circulating or tissue angiotensinogen may cause an increase in blood pressure in humans , even in the presence of a functionally active servo-mechanism to downregu late HREN expression.