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 containing the human renin (HREN) gene and extending to -35 and -75 kilobase pairs, respectively. HREN protein production was restricted to juxtaglomerular cells of the kidney, and its expression was tightly regulated by angiotensin 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, suggesting tight physiological regulation. P1 artificial chromosome mice were mated with transgenic mice overexpressing human angiotensinogen to determine if there was a chronic compensatory down-regulation of the transgene. Despite a 3-fold down-regulation of HREN mRNA, plasma angiotensin II and blood pressure was modestly elevated in the double transgenic mice. Nevertheless, this elevation was significantly less than a different double transgenic model containing a poorly regulated HREN transgene. The increase in blood pressure, despite the decrease in HREN mRNA, suggests that the HREN gene can partially, but not completely, compensate for excess circulating angiotensinogen. 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 down-regulate HREN expression.
Sinn
P L
PL
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Davis
D R
DR
Sigmund
C D
CD
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D017101:Bacteriophage P1; D020029:Base Pairing; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007606:Juxtaglomerular Apparatus / Q000201:enzymology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D012083:Renin / Q000235:genetics*; D012964:Sodium / Q000502:physiology
D000804:Angiotensin II; D002216:Captopril; D012964:Sodium; D012083:Renin