title: Response to genetic manipulations of liver angiotensinogen in the physiological range.
abstract: Genetic variation in the human angiotensinogen gene (AGT) influences plasma AGT concentration and susceptibility to essential hypertension by a mechanism that remains to be clarified. When one or two additional copies of the gene were inserted by gene titration (by homologous recombination with gap-repair at the AGT locus), both plasma AGT and arterial pressure were elevated in the physiological range in the mouse. The causal dependency between plasma AGT and blood pressure and the relative contribution of the various tissues that express AGT to these two phenotypic parameters remained to be determined. To address these issues, we generated a transgenic mouse with overexpression of the mouse AGT gene restricted to the liver. The transgene was examined in two contrasted genetic backgrounds, the sodium-sensitive C57BL/6J and the sodium-resistant A/J. Transgenic and control male animals underwent continuous cardiovascular monitoring by telemetry for 14 days while under a standard sodium diet (0.2%). Moderate but significant increases in plasma AGT (40%, p = 0.01) and systolic blood pressure (4-6 mmHg, p ranging from 0.01 to <0.001) were observed in the sodium-sensitive background, but not in the sodium-resistant animals. Statistical analysis of a large number of consecutive, repeated measurements of blood pressure afforded power to detect small effects in the physiological range by use of advanced mixed models of analysis of variances and covariances. Although plasma renin activity was increased in the sodium-sensitive background, it did not reach statistical significance. These observations underline a potential contribution of systemic AGT to the mechanism of AGT-mediated hypertension, but the significance of sodium sensitivity in the genetic background suggests participation of the kidney in expression of the elevated blood pressure phenotype, a matter that will warrant further studies. They also highlight the challenge of identifying the contribution of individual genes in complex inheritance, as their effects are modulated by other genetic and environmental determinants.
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Barbu
authors.initials: B
authors.lastname: Gociman
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rohrwasser
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hillas
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Hunter
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hunter
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lott
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Smith
authors.initials: S
authors.lastname: Monson
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Human Genetics, University of Utah, Health Sciences Center, Eccles Institute of Human Genetics, 6th floor, Salt Lake City, UT, 84112, USA. jml@genetics.utah.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Lalouel
mesh_terms: D000450:Aldosterone / Q000652:urine; D000808:Angiotensinogen / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D018628:Gene Dosage / Q000502:physiology*; D005818:Genetic Engineering / Q000379:methods; D006973:Hypertension / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
chemical_list: D000808:Angiotensinogen; D000450:Aldosterone