Genetic manipulation of the renin-angiotensin system

Doan, Thanh N.; Gletsu, Nana; Cole, Justin M.; Bernstein, Kenneth E.

doi:10.1097/00041552-200107000-00002

Cited by 26 publications

(18 citation statements)

References 40 publications

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“…In addition, genetic manipulation leading to overactivity of AT 1a receptors in mice results in an increase in haematocrit [31]. Conversely, AT 1 -receptor-KO (knockout) mice show a decrease in haematocrit EPC apoptosis and senescence [76][77][78] Neointima formation or inflammation by VSMC-like Pro-angiogenic EPC stimulation [73,74] Fibrocyte-related fibrosis progenitor cells [168][169][170] [134,[136][137] Promotes adipocyte formation [160] Inhibits cardiomyocyte formation [142] [53] values when compared with WT (wild-type) animals [32]. The stimulatory role of AT 1 receptors in erythropoiesis has clinical implications: as with ACEis, ARB treatment was reported to reduced erythropoiesis in healthy individuals and also in patients undergoing haemodialysis [33].…”

Section: Erythropoiesismentioning

confidence: 99%

The renin–angiotensin system, bone marrow and progenitor cells

Durik¹,

Pessôa²,

Roks³

2012

Clinical Science

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Modulation of the RAS (renin–angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1–7) [angiotensin-(1–7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1–7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1–7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications.

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Section: Erythropoiesismentioning

confidence: 99%

The renin–angiotensin system, bone marrow and progenitor cells

Durik¹,

Pessôa²,

Roks³

2012

Clinical Science

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“…Moreover, knockout mice for well-known ACE substrates, such as angiotensinogen and bradykinin, never show impaired male fertility, suggesting substrates specific for tACE [19,20].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidase-Inactivated tACE Action In Vivo: Selective Inhibition of Sperm-Zona Pellucida Binding in the Mouse1

Deguchi¹,

Tani²,

Watanabe³

et al. 2007

Biology of Reproduction

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The angiotensin-converting enzyme (ACE) plays a crucial role in male fertilization and is a key regulator of blood pressure. Testicular ACE (tACE), the germinal specific isozyme expressed on different promoters, exclusively carries out the role of ACE in fertility, although the site and mode of action are not well known. To investigate the contribution of tACE in fertilization, we produced transgenic mouse lines carrying a dipeptidase-inactivated mutant. Although the transgenic mice showed normal blood pressure, kidney morphology, and fertility, reduced fertilization was observed after in vitro fertilization (IVF). The sperm-zona pellucida (ZP) binding was exclusively impaired in these lines in a manner similar to that observed in an Ace knockout mouse. The dipeptidase activity was reduced in epididymal ingredients but not in the testis. Furthermore, direct application of mutant protein did not suppress sperm-ZP binding of intact sperm during IVF, implying that the dipeptidase-inactivated mutant affects sperm modification in the epididymis for ZP binding. Our results indicate that the dipeptidase-inactivated tACE acts in vivo, suggesting that tACE contributes to fertilization as a dipeptidase at least in the epididymis.

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“…On the question of ACE gene association with IgAN progression, the results were also conflicting, with three (including the present study) of the five studies reporting no association. Given that the ACE gene polymorphism accounted for half of the total phenotypic variance of serum ACE, the prominent role of RAS in blood pressure control and glomerular hemodynamics [37]and the effectiveness of ACE inhibitors on proteinuria [16], the evidence on balance suggest that ACE gene polymorphism may confer some degree of susceptibility to IgAN and may have some limited impact on disease progression. However, in the present of other risk factors which were not uniformly controlled in every study, its weak influence may not be consistently detectable and hence the conflicting results from different studies.…”

Section: Discussionmentioning

confidence: 99%

Renin-Angiotensin System Gene Polymorphisms: Its Impact on IgAN and Its Progression to End-Stage Renal Failure among Chinese in Singapore

Lau¹,

Woo²,

Choong³

et al. 2004

Nephron Physiol

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Background: Gene polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (ATR) had been associated with IgA nephropathy (IgAN) and its progression. Several studies on Caucasian and Japanese had reported contradicting results. We determined these polymorphisms in 118 Chinese patients with IgAN and 94 healthy Chinese to assess their clinical impact. Methods: Genotyping was performed with DNA from peripheral leukocytes, PCR amplification of the polymorphic sequence, restriction enzymes digestion, separation and identification of DNA fragments. Clinical data at renal biopsy and final status on renal function were determined from patients’ records. Results: Among controls, genotype distributions were in Hardy-Weinberg equilibrium. Comparing all IgAN patients with controls, AGT and ATR genotype distributions were similar whereas there was significant increase in the ACE DD genotype (p < 0.05). Comparing patients with end-stage renal failure (IgAN-ESRF) and without (IgAN-nonESRF), there was no difference in any of the three gene polymorphisms. But in contrast, there were significant differences in higher male prevalence (p < 0.05), increased serum creatinine at presentation (p < 0.05), more sclerosis (p < 0.01) and higher tubulointerstitial lesion score (p < 0.001) in the IgAN-ESRF group. Conclusion: Among the ACE, AGT and ATR gene polymorphisms, only the DD genotype may predispose the individual to IgAN in our Chinese population. In contrast to clinical and histological risk factors, these genetic variations showed no impact on disease progression to ESRF. It is unlikely that genotyping more patients will prove these genes useful. Nevertheless, preclinically determined genetic markers are very useful as risk factors for disease occurrence and as prognostic indices for disease progression. Therefore, continuing efforts should be made to look at other genes to find those with significance.

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Genetic manipulation of the renin-angiotensin system

Cited by 26 publications

References 40 publications

The renin–angiotensin system, bone marrow and progenitor cells

The renin–angiotensin system, bone marrow and progenitor cells

Dipeptidase-Inactivated tACE Action In Vivo: Selective Inhibition of Sperm-Zona Pellucida Binding in the Mouse1

Renin-Angiotensin System Gene Polymorphisms: Its Impact on IgAN and Its Progression to End-Stage Renal Failure among Chinese in Singapore

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