Alternative Splicing of the mRNA Coding for the Human Endothelial Angiotensin-Converting Enzyme: A New Mechanism for Solubilization

Sugimura, Keiichi; Tian, Xiao-Li; Hoffmann, Sigrid; Ganten, Detlev; Bäder, Michael

doi:10.1006/bbrc.1998.8813

Cited by 28 publications

(18 citation statements)

References 37 publications

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“…Kendall and Thomas have shown suppression of endothelial cell growth factor activity by a secreted splice variant of vascular endothelial cell growth factor receptor lacking the transmembrane domain. 24 In addition, similar transmembrane-negative modifications generated by alternative splicing have been reported, e.g., for the T-cell receptor, 25 angiotensin-converting enzyme, 26 and interleukin-6 receptor. 27 Furthermore, the distinct functional role of such splicing variants was recently shown for the soluble receptor of advanced glycosylation, 28 which appears to be an important physiological mechanism regulating atherogenesis in hyperglycemia.…”

Section: Discussionsupporting

confidence: 55%

Cloning and Expression of the Rat Nephrin Homolog

Ahola¹,

Wang²,

Luimula³

et al. 1999

The American Journal of Pathology

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Despite of the increased availability of genetically modified mouse strains , the experimental models in the rat have provided the most widely employed and versatile models for the study of renal pathophysiology and functional genetics. The identification of the human gene mutated in the congenital nephrotic syndrome of the Finnish type (NPHS1) has recently been reported , and its protein product has been termed nephrin. Here we report the molecular cloning and characterization of rat nephrin cDNA. Rat nephrin cDNA has an open reading frame of 3705 bp , shows 82% sequence identity with human nephrin cDNA, and shows characteristic rat-specific splicing variants. The translated nucleotide sequence has 89% sequence identity at the amino acid level. The signal sequence , glycosylation , and cysteine localization patterns are nearly identical to those of human nephrin. As in the human , the rat nephrin transcript is expressed in a tissue-restricted pattern. Antipeptide antibodies raised to the intracellular nephrin-specific domain identified immunoreactivity exclusively within the rat kidney glomerulus by indirect immunofluorescence. Initial results with semiquantitative reverse transcriptase-polymerase chain reaction analysis showed a remarkable down-regulation of nephrin-specific mRNA in the puromycin nephrosis of the rat. (Am J Pathol 1999, 155:907-913)The molecular pathogenesis of diseases that result in abnormalities of glomerular filtration has remained poorly understood. Recent results indicate that podocytes play an important role in regulating the passage of macromolecules and have several structural properties suitable for allowing the rapid modulation of the permeability barrier.

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Section: Discussionsupporting

confidence: 55%

Cloning and Expression of the Rat Nephrin Homolog

Ahola¹,

Wang²,

Luimula³

et al. 1999

The American Journal of Pathology

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“…Three ACE gene polymorphisms, spanning approximately 8 kb and located downstream from the ACE Ins/Del (on intron 16) previously shown to predict in-vivo ACE plasma levels [12], and one of which is near a potential alternative ACE mRNA splice site [13], were selected: G12269A, a G to A polymorphism 12269 base pairs from the ATG translational start site (RefSNP or rs4344, located on intron 18 and the closest single nucleotide polymorphism (SNP) to the ACE Ins/Del on intron 16); C17888T, (rs4359, located on intron 23); and G20037A, (rs4363, located on intron 25 and near the splice acceptor site for terminal exon 26, which encodes the membrane-spanning carboxyl-terminus) [13] (Table 1 and Fig. 2).…”

Section: Geneticsmentioning

confidence: 99%

“…Based on our preliminary results (not shown here), G12269A was in nearly complete linkage disequilibrium with the ACE Ins/Del polymorphism (D′ = 0.98). It has been suggested that the Ins/Del polymorphism may regulate alternative ACE mRNA splicing [13]. If this were so, individuals with an Ins/Ins or Del/Del homozygous diploid genotype would express identical copies of the same ACE mRNAs and, ultimately, ACE proteins; those with an Ins/Del genotype, on the other hand, might express two different versions of the ACE protein.…”

Section: Unique Study Features Heterosismentioning

confidence: 99%

“…Therefore, we used a relatively novel approach and applied survival methodology by focusing on the time to reach a target blood pressure goal (in this case, a mean arterial pressure or MAP of ≤107 mmHg). We also concentrated on specific polymorphisms in the region of the gene encoding the catalytically active domain, and just downstream from the Ins/Del that have been previously related to ACE plasma levels [12], as well as alternative splicing of the ACE mRNA [13].…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial

Bhatnagar

O’Connor

Schork

et al. 2007

Journal of Hypertension

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Objective-It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor.Methods-Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure (≤ 107 mmHg) was analyzed by genotype and ACE haplotype using Kaplan-Meier survival curves and Cox proportional hazard models.Results-Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32-3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13-1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification.Conclusions-African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing.Correspondence to Vibha Bhatnagar, MD, MPH, VA San Diego Healthcare System,

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“…The presence of 90 kDa and 65 kDa ACE has been the target of several studies. The literature suggests that mechanisms of solubilization are involved in forming these isoforms by shedding with a secretase or (35-37), by an alternative splicing of the ACE mRNA (38,39).Patients with the ACE90 kDa+ had a significantly reduced endothelium-dependent vasodilatation response of the brachial artery when compared with patients without this isoform (ACE 90 kDa-): 11.4% ± 5.3% compared with 17.6% ± 7.1%, P = 0.014, respectively. Patients with 90 kDa ACE associated with a family history of hypertension also had a negative impact on FMD and the percentage was: 12.4% ± 5.6% in FH+ /ACE90+ compared with 17.7% ± 6.2% in FH-/ACE90-group (P < 0.05).…”

mentioning

confidence: 99%

Association of Urinary N-Domain Angiotensin I-Converting Enzyme with Plasma Inflammatory Markers and Endothelial Function

Fernandes

Plavnik

Teixeira

et al. 2008

Mol Med

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The aim of this study was to investigate the association between urinary 90 kDa N-domain Angiotensin I-converting enzyme (ACE) form with C-reactive protein (CRP) and homocysteine plasma levels (Hcy), urinary nitric oxide (NOu), and endothelial function (EF) in normotensive subjects. Forty healthy subjects were evaluated through brachial Doppler US to test the response to reactive hyperemia and a panel of blood tests to determine CRP and Hcy levels, NOu, and urinary ACE. They were divided into groups according to the presence (ACE90+) or absence (ACE90-) of the 90 kDa ACE, the presence (FH+) or absence (FH-) of family history of hypertension, and the presence or absence of these two variables FH+/ACE90+ and FH-/ACE90-. We found an impaired endothelial dilatation in subjects who presented the 90 kDa N-domain ACE as follows: 11.4% ± 5.3% in ACE90+ compared with 17.6% ± 7.1% in ACE90-group and 12.4% ± 5.6% in FH+/ACE90+ compared with 17.7% ± 6.2% in FH-/ACE90-group, P < 0.05. Hcy and CRP levels were statistically significantly lower in FH+/ACE90+ than in FH-/ACE90-group, as follows: 10.0 ± 2.3 μM compared with 12.7 ± 1.5 μM, and 1.3 ± 1.8 mg/L compared with 3.6 ± 2.0 mg/L, respectively. A correlation between flowmediated dilatation (FMD) and CRP, Hcy, and NOu levels was not found. Our study suggests a reduction in the basal NO production confirmed by NOu analysis in subjects with the 90 kDa N-domain ACE isoform alone or associated with a family history of hypertension. Our data suggest that the presence of the 90 kDa N-domain ACE itself may have a negative impact on flowmediated dilatation stimulated by reactive hyperemia. Online address: http://www.molmed.org doi: 10.2119/2007-00112. Fernandes NO synthesis may be the first detectable evidence of endothelial dysfunction. ED is present in healthy normotensive subjects who are at high risk for the development of essential hypertension (18).Although there is a general agreement that endothelium-dependent vasodilatation is impaired in patients with essential hypertension, the relationship between this defect and plasma concentrations of nitric oxide is unclear (17).Most cardiovascular risk factors have been recognized to promote a proinflammatory state (19). Among them, arterial hypertension has been related to many circulating inflammatory markers such as C-reactive protein (CRP) and homocysteine (Hcy), (20)(21)(22) independently of other risk factors, promoting the idea of hypertension as a potentially pro-inflammatory condition (22). Studies have clearly established that CRP predicts a future risk of cardiovascular disease in apparently healthy people (23). The mechanism linking Hcy with cardiovascular disease may be the induction of vascular damage, although the exact mechanism is not understood fully. On the other hand, some prospective studies have shown only a weak or no relationship between homocysteine and cardiovascular disease (24).Our purpose is to test the hypothesis that the presence of the 90 kDa Ndomain ACE form in human urine could be associated with...

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Alternative Splicing of the mRNA Coding for the Human Endothelial Angiotensin-Converting Enzyme: A New Mechanism for Solubilization

Cited by 28 publications

References 37 publications

Cloning and Expression of the Rat Nephrin Homolog

Cloning and Expression of the Rat Nephrin Homolog

Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial

Association of Urinary N-Domain Angiotensin I-Converting Enzyme with Plasma Inflammatory Markers and Endothelial Function

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