Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes.

Ohkubo, Hiroaki; Kawakami, Hideshi; Kakehi, Yoshiyuki; Takeuchi, Takumi; Arai, Hidee; Yokota, Yoshifumi; Iwai, Masaru; Tanabe, Yuji; Masu, Masayuki; Hata, Jun-ichiro

doi:10.1073/pnas.87.13.5153

Cited by 127 publications

(42 citation statements)

References 16 publications

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“…2 Recently, the potential contribution of angiotensinogen in the pathogenesis of hypertension has been suggested by genetic approaches. 2,3 The findings of some studies using transgenic animals and a linkage analysis for the angiotensinogen gene 3,4 also support this hypothesis. Regarding the role of circulating angiotensinogen in the pathogenesis of hypertension, an efficient gene transfer method mediated by a viral liposome complex has been recently used as a delivery system of antisense ODNs in vivo.…”

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confidence: 67%

Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats

et al. 1998

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Abstract-In the renin-angiotensin system, renin is known to cleave angiotensinogen to generate angiotensin I, which is the precursor of angiotensin II. Angiotensin II is a vasoactive peptide that plays an important role in blood pressure. On the other hand, the liver is the major organ responsible for the production of angiotensinogen in spontaneously hypertensive rats (SHR). To test the hypothesis that a reduction of angiotensinogen mRNA in the liver by antisense oligodeoxynucleotides (ODNs) may affect both plasma angiotensinogen and angiotensin II levels, as well as blood pressure, we intravenously injected antisense ODNs against rat angiotensinogen coupled to asialoglycoprotein carrier molecules, which serve as an important regulator of liver gene expression, into SHR via the tail vein. The SHR used in the present study were studied at 20 weeks of age and were fed a standard diet throughout the experiment. Plasma angiotensinogen, angiotensin II concentrations, and blood pressure all decreased from the next day until up to 5 days after the injection of antisense ODNs. These concentrations thereafter returned to baseline by 7 days after injection. A reduction in the level of hepatic angiotensinogen mRNA was also observed from the day after injection until 5 days after injection with antisense ODNs. However, in the SHR injected with sense ODNs, plasma angiotensinogen, angiotensin II concentrations, and blood pressure, as well as hepatic angiotensinogen mRNA, did not significantly change throughout the experimental period. Although the exact role of angiotensinogen in hypertension still remains to be clarified, these findings showed that intravenous injection with antisense ODNs against angiotensinogen coupled to asialoglycoprotein carrier molecules targeted to the liver could thus inhibit plasma angiotensinogen levels and, as a result, induce a decrease in blood pressure in SHR. (Hypertension. 1998;31:1166-1170.)

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confidence: 67%

Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats

et al. 1998

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“…Ohkubo et al (33) previously reported elevated systolic blood pressure in transgenic mice containing both the rat renin and rat angiotensinogen genes. As in our experiments, trans- Figure 5.…”

Section: Discussionmentioning

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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“…This permanent hypertension is unusual because of its early development, the absence of aggravation during mouse life, its moderate severity, and its predominance in males. The roles of various genes of the RAS that are potentially involved in the control of BP (renin, angiotensinogen, angiotensin-converting enzyme, and AT 1 genes) has been extensively investigated both by overexpression and by inactivation in mice and rats (20)(21)(22)(23)(24)(25)(26). Inactivation of the Agtr1a gene (27) but not the Agtr1b (7) or the Agtr2 (28, 29) genes, causes a BP decrease, and the duplication of Agtr1a gene results in a moderate increase of BP in female mice (8).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Billet¹,

Bardin²,

Verp³

et al. 2007

J. Clin. Invest.

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The role of the renin-angiotensin system has been investigated by overexpression or inactivation of its different genes in animals. However, there is no data concerning the effect of the constitutive activation of any component of the system. A knockin mouse model has been constructed with a gain-of-function mutant of the Ang II receptor, type 1A (AT 1A ), associating a constitutively activating mutation (N111S) with a C-terminal deletion, which impairs receptor internalization and desensitization. In vivo consequences of this mutant receptor expression in homozygous mice recapitulate its in vitro characteristics: the pressor response is more sensitive to Ang II and longer lasting. These mice present with a moderate (~20 mmHg) and stable increase in BP. They also develop early and progressive renal fibrosis and cardiac fibrosis and diastolic dysfunction. However, there was no overt cardiac hypertrophy. The hormonal parameters (lowrenin and inappropriately normal aldosterone productions) mimic those of low-renin human hypertension. This new model reveals that a constitutive activation of AT 1A leads to cardiac and renal fibrosis in spite of a modest effect on BP and will be useful for investigating the role of Ang II in target organs in a model similar to some forms of human hypertension. IntroductionThe Ang II receptor, type 1 (AT 1 ), is a G protein-coupled receptor (GPCR) that transduces the main physiological actions of the renin-angiotensin system (RAS) in target cells. The major signaling events following agonist binding to this receptor are activation of phospholipase C via a Gq protein, mobilization of the calcium intracellular stores, and activation of protein kinase C. MAP kinase and Jak/STAT pathways are also activated and may participate in the hypertrophic actions of Ang II (1). There are 2 AT 1 subtypes in rodents, AT 1A and AT 1B (2, 3); the tissue distribution of the 2 subtypes (4) and knockout experiments in mice (5-7) indicate that cardiovascular, renal, and adrenal actions of Ang II are mainly mediated by AT 1A . The unambiguous role of AT 1 in controlling BP is evidenced in numerous animal models. For example, the knockout of AT 1A in mouse reduces BP (5, 6), and its overexpression by gene duplication increases BP in female mice (8). This role contrasts with the absence of clear involvement of renin angiotensin genes in genetic forms of human hypertension (9).The concept of constitutive activation is an important breakthrough in the understanding of GPCR molecular functions: point mutations stabilize the receptor in an active conformation independent of ligand, resulting in a permanent activation of the

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Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes.

Cited by 127 publications

References 16 publications

Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats

Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats

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

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

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