Male–female differences in fertility and blood pressure in ACE-deficient mice

Krege, John H.; John, Simon W. M.; Langenbach, Laura L.; Hodgin, Jeffrey B.; Hagaman, John R.; Bachman, Eric; Jennette, J. Charles; O’Brien, Deborah A.; Smithies, Oliver

doi:10.1038/375146a0

Cited by 609 publications

(434 citation statements)

References 23 publications

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“…These observations contrast with mice lacking all ACE who have both renal developmental defects and are unable to effectively concentrate urine. 2,3 Thus, the generation of angiotensin II in tissue locations independent of the renal parenchyma appears capable of maintaining cardiovascular homeostasis, including normal renal function.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Each of these parameters was studied in the ACE 8/8 mice. Systolic blood pressure was evaluated in conscious wild-type, heterozygous, and ACE 8/8 mice (Figure 6a).…”

Section: Physiological Measurementsmentioning

confidence: 99%

“…Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease.…”

mentioning

confidence: 99%

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Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

231

191

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To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

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Section: Discussionmentioning

confidence: 99%

“…2,3 Each of these parameters was studied in the ACE 8/8 mice. Systolic blood pressure was evaluated in conscious wild-type, heterozygous, and ACE 8/8 mice (Figure 6a).…”

Section: Physiological Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

231

191

View full text Add to dashboard Cite

show abstract

“…To date, a direct link between a particular gene impinging histone modifications to BP has not been clearly established. Second, numerous mouse models lacking ENaC and their direct or indirect regulators such as AS, 13 angiotensinogen (Agt), 14 angiotensin-converting enzyme (ACE), 15 MR, 16 Sgk1, 17 WNK1, 18 WNK4, 19 and Period 20 have been reported. However, the role of these models in showing the epigenetic control of BP is still unclear.…”

mentioning

confidence: 99%

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

Chen¹,

H²,

Pochynyuk

et al. 2011

Journal of the American Society of Nephrology

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The putative transcription factor AF17 upregulates the transcription of the epithelial sodium channel (ENaC) genes, but whether AF17 modulates sodium homeostasis and BP is unknown. Here, we generated Af17-deficient mice to determine whether deletion of Af17 leads to sodium wasting and low BP. Compared with wild-type mice, Af17-deficient mice had lower BP (11 mmHg), higher urine volume, and increased sodium excretion despite mildly increased plasma concentrations of aldosterone. Deletion of Af17 led to increased dimethylation of histone H3 K79 and reduced ENaC function. The attenuated function of ENaC resulted from decreased ENaC mRNA and protein expression, fewer active channels, lower open probability, and reduced effective activity. In contrast, inducing high levels of plasma aldosterone by a variety of methods completely compensated for Af17 deficiency with respect to sodium handling and BP. Taken together, these data identify Af17 as a potential locus for the maintenance of sodium and BP homeostasis and suggest that a particular histone modification is directly linked to these processes. Af17-mediated regulation of BP is largely, but not exclusively, the result of modulating ENaC, suggesting it has potential as a therapeutic target for the control of BP.

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“…Linkage studies in rodents (14,15) and case-control studies in humans (16,17) have suggested that sequences at, or linked to, the ACEgene (Ace) can influence blood pressure. The disruption of the Ace gene in mice demonstrated that the null mutants have comparably low blood pressure with Agt mutant (Agt-/~) mice (18,19).…”

Section: Confirmation Of Predicted Functions Of Ang IImentioning

confidence: 99%

What Have We Learned from Gene Targeting Studies for the Renin Angiotensin System of the Kidney?

Nishimura

Ichikawa

1999

Intern. Med.

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Over the last decade, gene targeting technologies have provided investigators with powerful new tools to study the physiology and pathophysiology of the kidney. In that, the renin-angiotensin system (RAS) has been a subject of intense investigation. Detailed analyses of mutant mice have not only confirmed notions already suggested by other studies, but also shed a new light on previously unrecognized functions of RAS.In this review, wewill focus on what wehave learned from these gene targeted animals in particular relevance to nephrology. (Internal Medicine 38: 315-323, 1999)

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Male–female differences in fertility and blood pressure in ACE-deficient mice

Cited by 609 publications

References 23 publications

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

What Have We Learned from Gene Targeting Studies for the Renin Angiotensin System of the Kidney?

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