Modulation of mouse renin gene expression by dietary sodium chloride intake in one-gene, two-gene and transgenic animals

Miller, Christopher C.J.; Samani, Nilesh J.; Carter, Andrew T.; Brooks, Jeanie I.; Brammar, William J.

doi:10.1097/00004872-198911000-00002

Cited by 19 publications

(12 citation statements)

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“…The other possibility is that human renin may feed back to the mouse renin system, either directly through some unidentified mechanism or by cleavage of mouse AGT to produce Ang I. It has been reported that overexpression of a nonprocessable form of mouse prorenin in transgenic mice is associated with a suppression of renin activity from the endogenous mouse gene, 35 suggesting the existence of a direct mechanism. Although we have never been able to detect cleavage of rodent substrate by human renin in vitro, prolonged incubation in plasma in vivo might initiate the formation of sufficient Ang II to suppress renin secretion and synthesis as part of the normal homeostatic feedback control.…”

Section: Discussionmentioning

confidence: 99%

Appropriate Regulation of Human Renin Gene Expression and Secretion in 45-kb Human Renin Transgenic Mice

Yan

Chen

et al. 1998

Hypertension

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Abstract-To create physiological models of the human renin-angiotensin system in transgenic animals, the component genes should be expressed in the correct tissues and cells and respond appropriately to physiological stimuli. We recently showed that mice carrying a 45-kb human renin genomic fragment, containing approximately 25 kb 5Ј-flanking DNA and 6 kb 3Ј-flanking DNA, express the transgene in a highly cell-and tissue-specific pattern. More importantly, in contrast to previous models, human renin in the circulating plasma of these mice is derived exclusively from the kidneys. In the present study, we tested the responses of both human and mouse renal renin expression and secretion of the 45-kb hREN transgenic mice to a variety of physiological and pharmacological stimuli. A sodium-deficient diet, angiotensin-converting enzyme inhibition, and ␤ 1 -adrenergic stimulation each increased both human and mouse plasma renin concentration significantly, whereas elevated blood pressure and/or increased plasma angiotensin II levels suppressed them. Human and mouse renal renin mRNA levels changed similarly but to a lesser degree. These studies demonstrate that human renin synthesis and secretion respond appropriately in 45-kb hREN mice to physiological stimuli. This most likely results from appropriate cell-specific expression of the transgene conferred by the extended transgene flanking sequences. (Hypertension. 1998;32:205-214.)

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Section: Discussionmentioning

confidence: 99%

Appropriate Regulation of Human Renin Gene Expression and Secretion in 45-kb Human Renin Transgenic Mice

Yan

Chen

et al. 1998

Hypertension

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“…The renin-angiotensin system (RAS) 1 is well recognized as an important factor in the control of arterial pressure through numerous physiological, molecular biological, and molecular genetic studies. The obvious nature of the RAS as a candidate system for the etiology of hypertension has prompted a number of investigators to examine this system at the molecular biologic and molecular genetic level, and several important findings have resulted from these studies.…”

Section: Introductionmentioning

confidence: 99%

“…The obvious nature of the RAS as a candidate system for the etiology of hypertension has prompted a number of investigators to examine this system at the molecular biologic and molecular genetic level, and several important findings have resulted from these studies. First, the levels of mRNAs encoding renin, angiotensinogen, and angiotensinconverting enzyme (ACE) are significantly altered in some tissues of experimentally hypertensive and genetically hypertensive rats when compared with their normotensive counterparts (1)(2)(3)(4)(5). Second, centrally administered antisense oligonucleotides to angiotensinogen are effective in lowering blood pressure in spontaneously hypertensive rats (6).…”

Section: Introductionmentioning

confidence: 99%

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Merrill¹,

Thompson²,

Carney³

et al. 1996

J. Clin. Invest.

170

192

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We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1 c allele or in mice containing one copy each of Ren-1 c , Ren-1 d , or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renindependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system. ( J. Clin. Invest. 1996. 97:1047-1055.)

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“…However, this process is tightly regulated as Ang-II elicits negative feedback on both primary renin synthesis and renin secretion in juxtaglomerular (JG) cells, thereby providing a means of autoregulation (5). In addition, renin production and secretion are tightly regulated in response to changes in arterial pressure and plasma sodium levels (6,7). Therefore, gaining a clear understanding of renin gene regulation in response to physiological cues such as Ang-II is essential if we are to understand how perturbations in this homeostatic system lead to cardiovascular disease.…”

mentioning

confidence: 99%

Highly Regulated Cell Type-restricted Expression of Human Renin in Mice Containing 140- or 160-Kilobase Pair P1 Phage Artificial Chromosome Transgenes

Sinn

Davis

Sigmund

1999

Journal of Biological Chemistry

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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 downregulate HREN expression.

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Modulation of mouse renin gene expression by dietary sodium chloride intake in one-gene, two-gene and transgenic animals

Cited by 19 publications

References 0 publications

Appropriate Regulation of Human Renin Gene Expression and Secretion in 45-kb Human Renin Transgenic Mice

Appropriate Regulation of Human Renin Gene Expression and Secretion in 45-kb Human Renin Transgenic Mice

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Highly Regulated Cell Type-restricted Expression of Human Renin in Mice Containing 140- or 160-Kilobase Pair P1 Phage Artificial Chromosome Transgenes

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