Abstract
Here we investigate the biochemical, molecular, and cellular changes directed toward blood pressure homeostasis that occur in the endocrine branch of the renin-angiotensin system of mice having one angiotensinogen gene inactivated. No compensatory up-regulation of the remaining normal allele occurs in the liver, the main tissue of angiotensinogen synthesis. No significant changes occur in expression of the genes coding for the angiotensin converting enzyme or the major pressor-mediating receptor for angiotensin, but plasma renin concentration in the mice having only one copy of the angiotensinogen gene is greater than twice wild-type. This increase is mediated primarily by a modest increase in the proportion of renal glomeruli producing renin in their juxtaglomerular apparatus and by four times wild-type numbers of renin-producing cells along afferent arterioles of the glomeruli rather than by up-regulating renin production in cells already committed to its synthesis.
Highlights
An essential feature of complex organisms is the ability to maintain near constancy of their internal environments
Genetic heterogeneity has been demonstrated at the angiotensinogen locus in humans [1, 2], and two common alleles are associated with quantitative differences in the plasma concentration of AGT and with differences in blood pressure
A comparison of AGT levels in wild-type inbred strain B6 and 129 mice shows that B6 mice have higher AGT levels (558 Ϯ 30 angiotensin I (AngI) ng/ml/h, in six females) than do 129 mice (426 Ϯ 11 AngI ng/ml/h, in six females), so that if strain differences in angiotensinogen gene (Agt) gene expression persist in the F1 hybrids, the AGT concentration in the Agt one-copy animals should be even more than 50% of the wild-type F1 animals
Summary
An essential feature of complex organisms is the ability to maintain near constancy of their internal environments. Homeostasis is maintained by the operation of sophisticated systems that permit desirable physiological changes in biological variables, but that act homeostatically if external factors cause undesirable changes in the variables Genetic heterogeneity, such as is inherent to all outbred species including humans, tends to cause variation in the internal environment. We have recently been carrying out experiments aimed at identifying genes whose quantitative expression affects an important biological variable, blood pressure To this end, we have used gene targeting in mice to alter the number of functional copies of several candidate genes, and so to produce systematic changes in their expression of the same order of magnitude as those occurring naturally in humans. In previous experiments [3, 4] quantitative differences in expression in mice of the angiotensinogen gene (Agt) have been shown to directly cause modest changes in blood pressure. We explore the long term homeostatic adjustments that occur in mice attempting to restore their blood pressures to normal in the face of inheriting below normal expression of the angiotensinogen gene (Agt)
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