Phenotypic inhibition of the renin-angiotensin system, emergence of the ren-2 gene, and adaptive radiation of mice

Weaver, Debbi; Skinner, Sandford L.; Walker, Lesley; Sangster, Mark Y.

doi:10.1016/0016-6480(91)90035-5

Cited by 29 publications

(19 citation statements)

References 26 publications

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“…Therefore, the dramatic increase in mouse renin activity after addition of rat angiotensinogen depends on both the increase in the substrate concentration in the assay and the increase in the speed of the renin reaction. Weaver et al 18 showed an elevation of the blood pressure of mice after injection of nephrectomized rat plasma, and Poulsen and Jacobsen 8 and we showed that mouse renin reacts faster with rat angiotensinogen than with the homologous substrate. Recently, Kimura et al 3 developed a hypertensive transgenic mouse by transfection with the rat angiotensinogen gene.…”

Section: Discussionsupporting

confidence: 48%

Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.

et al. 1994

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The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4±37.3 ng angiotensin I/mL, n=4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from T he renin-angiotensin system plays an important role in the development of hypertension. Recently, various transgenic animal models of hypertension have been developed 15 to elucidate the mechanisms of hypertension. The transgenic rat TGR-(mRen-2)27, in which the mouse Ren-2 renin gene that codes for mouse salivary gland and kidney renin is transfected into the genome of the Sprague-Dawley rat, was the first genetic hypertensive rat model. In this model an overexpression of the transgene is found in the adrenal glands, 2 and these rats show severe hypertension with remarkably high adrenal renin levels; however, the pathogenesis of the hypertension is not clear. We have reported that adrenal renin and circulating renin in TGR rats are probably derived primarily from the transfected mouse renin gene. 6 On the other hand, angiotensinogen in the TGR rat is solely rat angiotensinogen. It is known that mouse renin can generate angiotensin I (Ang I) by reacting with rat angiotensinogen.7 If the circulating renin in the TGR rat is mouse renin, then the kinetics of 253.4±66.7 to 225 000±48 000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 £iL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7±4.7 and 61.8±2.7 mm Hg, respectively, whereas injection of 200 JAL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat. From these measurements and from the kinetic parameters measured by Poulsen and Jacobsen (/ Hypertens. 1986;4:175-180), we conclude that the molar concentration of mouse renin in the TGR rat is low compared with that of rat renin (1.5 versus 5.0 pmol/L) but that this low level of circulating mouse renin contributes significantly to plasma renin activity in the TGR rat. The elevation of renin activity and resulting hypertension in the TGR rat therefore can be attributed to the enhan...

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Section: Discussionsupporting

confidence: 48%

Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.

et al. 1994

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“…Ang I generated was estimated by radioimmunoassay with an in-house antibody and a 125 I-Ang I tracer. 24,25 In this assay, 1 GU of standard hog renin generated 87 g Ang I/h, a value similar to that found by Devaux et al 26 (68 g Ang I/h), although incubated at pH 6.5. For kinetic studies, renin and aogen were serially diluted with PBS with bovine serum albumin (see Results) and keeping incubate volume and protein concentration constant.…”

Section: Renin Assay and Kineticssupporting

confidence: 86%

“…The low concentration of mouse aogen has been reported previously in several mouse strains. 25 These aogen preparations did not generate a blank when incubated for 12 hours The use of animals in these experiments was approved by the Animal Ethics Committee of the University of Melbourne. …”

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confidence: 99%

Hypertension in the (mRen-2)27 Rat Is Not Explained by Enhanced Kinetics of Transgenic Ren-2 Renin

2003

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Abstract-Enhanced efficiency of the reaction between transgenic Ren-2 mouse renin and endogenous rat angiotensinogen has been suggested as 1 mechanism that contributes to the accelerated hypertension and increased tissue angiotensin of the (mRen-2)27 transgenic rat. This was tested in a study conducted at pH 7.4 in vitro that compared the kinetic constants of purified mouse Ren-2 and rat renin (each at 100, 75, 50, and 25 pmol/L) reacting with physiologic concentrations of rat angiotensinogen (0 to 4 mol/L). Under these conditions, the kinetic constants for Ren-2 (K m , 1.8 mol/L; K cat , 0.07/s; and K cat /K m , 0.04 L · mol Ϫ1 · s Ϫ1 ) were not different from rat renin. However, Ren-2 renin acting on its homologous mouse angiotensinogen was confirmed as being much slower. We conclude that hypertension in the Ren-2 rat is not related to renin kinetics. Other mechanisms are considered, with reference to human essential hypertension. Key Words: renin-angiotensin system Ⅲ angiotensinogen Ⅲ blood pressure Ⅲ hypertension, essential T he hypertensive (mRen-2)27 transgenic rat (Ren-2 rat) developed by Mullins et al 1 displays strong expression of the mouse Ren-2 transgene in several extrarenal tissues, 2 suppressed endogenous renal renin, and predominantly mouse inactive prorenin in the circulation secreted from extrarenal sources. [3][4][5] Most evidence indicates that it is the active component of mouse Ren-2 renin in tissues and plasma, reacting with the endogenous rat angiotensinogen (aogen), that induces and sustains the hypertension through conventional angiotensin II (Ang II)-dependent mechanisms, in particular because the hypertension is readily controlled by inhibition of the renin-angiotensin system (RAS). 6 However, this concept is at odds with the initial published evidence of suppressed or normal active plasma renin and angiotensin peptides in the adult Ren-2 rat, 1,7,8 reports that encouraged a search for additional hypertensive mechanisms. This transgenic rat strain has now been used widely to study various conditions relating to activation of the tissue RAS, including angiogenesis, cytokine activation, and profibrotic and inflammatory pathologic states, making it important to understand fully the fundamental processes inducing the severe hypertension.That plasma Ang II is not suppressed is now apparent, with resting levels increased up to 4-fold in both young 9 and adult 10 Ren-2 rats. One would expect a similar elevation of plasma active renin, but this depends on the pH at which the activity is estimated, 11,12 because mouse and rat renins have different pH optima when acting on rat aogen (pH 8.5 and 6.5, respectively). 5,11,12 Measured at pH 7.4 the Ren-2 rat plasma renin reaction is a mixed activity, mainly owing to the mouse transgenic renin, 11 and increases in renin activity have been found under these physiologic conditions. The lower level of rat renin in plasma is consistent with its low but not absent level in the kidneys. 11,12 By comparison with other high-renin models that cause malignant...

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“…The proportionality of mAgt copy number and blood pressure in the RA ϩ mice was initially surprising since we previously reported that mouse renin mRNA is downregulated in the kidney of the double transgenics (19). In normal mice, however, plasma renin is high whereas plasma AGT is low (41,42). Evidently, even when renin mRNA is significantly downregulated, sufficient plasma renin remains so that as plasma AGT increases with increasing mAgt gene copy number, mAgt-derived Ang-II in excess of that produced from human AGT causes an increase in blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes.

Davisson¹,

Kim²,

Krege³

et al. 1997

J. Clin. Invest.

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The aim of this study was to determine whether elements of the human renin-angiotensin system (RAS) could functionally replace elements of the mouse RAS by complementing the reduced survival and renal abnormalities observed in mice carrying a gene-targeted deletion of the mouse angiotensinogen gene ( mAgt ). Double transgenic mice containing the human renin ( HREN ) and human angiotensinogen ( HAGT ) genes were bred to mice heterozygous for the mAgt deletion and the compound heterozygotes were identified and intercrossed. The resulting progeny ( n ϭ 139) were genotyped at each locus and the population was stratified into two groups: the first containing both human transgenes (RA ϩ ) and the second containing zero or one, but not both human transgenes (RA Ϫ ). Despite appropriate Mendelian ratios of RA Ϫ mice that were wildtype ( ϩ / ϩ ), heterozygous ( ϩ / Ϫ ), and homozygous ( Ϫ / Ϫ ) for the deletion of mAgt at birth, there was reduced survival of RA Ϫ mAgt Ϫ / Ϫ mice to adulthood ( P Ͻ 0.001 by 2 ). In contrast, we observed appropriate Mendelian ratios of RA ϩ mAgt ϩ / ϩ , RA ϩ mAgt ϩ / Ϫ , and RA ϩ mAgt Ϫ / Ϫ mice at birth and in adults ( P Ͼ 0.05 by 2 ). These results demonstrate that the presence of both human transgenes rescues the postnatal lethality in mAgt Ϫ / Ϫ mice. The renal histopathology exhibited by RA Ϫ mAgt Ϫ / Ϫ mice, including thickened arterial walls, severe fibrosis, lymphocytic infiltration, and atrophied parenchyma, was also rescued in the RA ϩ mAgt Ϫ / Ϫ mice. Direct arterial blood pressure recordings in conscious freely moving mice revealed that BP (in mmHg) varied proportionally to mAgt gene copy number in RA ϩ mice ( ‫ف‬ 20 mmHg per mAgt gene copy, P Ͻ 0.001). BP in RA ϩ mAgt Ϫ / Ϫ mice (132 Ϯ 3, n ϭ 14) was intermediate between wild-type (RA Ϫ mAgt ϩ / ϩ , 105 Ϯ 2, n ϭ 9) and RA ϩ mAgt ϩ / ϩ (174 Ϯ 3, n ϭ 10) mice. These studies establish that the human renin and angiotensinogen genes can functionally replace the mouse angiotensinogen gene, and provides proof in principle that we can examine the regulation of elements of the human RAS and test the significance of human RAS gene variants by a combined transgenic and gene targeting approach. ( J. Clin. Invest. 1997. 99:1258-1264.)

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Phenotypic inhibition of the renin-angiotensin system, emergence of the ren-2 gene, and adaptive radiation of mice

Cited by 29 publications

References 26 publications

Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.

Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.

Hypertension in the (mRen-2)27 Rat Is Not Explained by Enhanced Kinetics of Transgenic Ren-2 Renin

Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes.

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