Abstract-The aim of this study was to investigate the role of cytosolic calcium for renin gene expression in juxtaglomerular cells. For this purpose, we used the immortalized juxtaglomerular mouse cell line As4.1. To increase cytosolic calcium concentration, we treated the cells with thapsigargin and cyclopiazonic acid, inhibitors of the endoplasmatic reticulum CaϪ ATPase. Thapsigargin and cyclopiazonic acid inhibited renin gene expression in a characteristic time and concentration-dependent manner. This effect was concentration-dependently blocked by BAPTA-AM, an intracellular Ca 2ϩ chelator. Pharmacological blocking of protein kinase C activity by calphostin, Gö6976, and Gö6983 did not change the effect of thapsigargin on renin gene expression. Experiments with renin1 C -promoter-reporter constructs revealed that thapsigargin inhibited renin gene transcription. Analysis of deletion constructs of the renin1 C promoter indicated that regulatory elements involved in the calcium-mediated inhibition of renin gene transcription are located in the enhancer region of the renin gene and that Ն3 transcription factor-binding sites are involved in this process. In addition, thapsigargin reduced the renin mRNA half-life from 10 hours (control conditions) to 4 hours. Knockdown studies with small interfering RNA directed to dynamin-1 mRNA revealed that dynamin-1 is likely to be involved in the calcium-mediated destabilization of renin mRNA. These data suggest that calcium inhibits renin gene expression in juxtaglomerular cells via a concerted action of inhibition of renin gene transcription and destabilization of renin mRNA. Key Words: calcium Ⅲ renin-angiotensin-aldosterone system Ⅲ thapsigargin Ⅲ mRNA stability T he renin-angiotensin-aldosterone system is a major regulatory system controlling extracellular fluid volume and blood pressure. The activity of the renin-angiotensin-aldosterone system is rate limited by the activity of the protease renin. 1 Renin itself is also regulated by a variety of factors. In the past few years, our knowledge has increased substantially about the regulation of renin gene expression at the cellular level. [2][3][4] For the transcription of the mouse renin gene, 2 critical regions, a proximal promoter region at Ϫ197 to Ϫ50 bp and an enhancer element at Ϫ2866 to Ϫ2625 bp, have been identified. 4 Also, the regulation of the renin mRNA stability is influenced by various factors, among these, interacting partner proteins like MINT, dynamin, or nucleolin have been found to be involved in the stabilization process of the renin mRNA. 5 The focus of our study was to investigate the role of calcium in the regulation of renin gene expression. This is of particular interest, because vasoactive peptides like angiotensin II or endothelin-1, which are known to be direct regulators of renin gene expression, activate the phospholipase C via a G protein-coupled receptor and, in turn, increase inositol triphosphate and diacylglycerol (DAG). 3 Whereas DAG is known to activate protein kinase C, inositol triphosp...
BackgroundAAA is a disease affecting predominantly male patients ≥65 years and its dreaded complications such as rupture led to population-based screening programs as preventive measure. Nonetheless, the supposed prevalence may have been overestimated, so that targeted screening of high risk populations may be more effective.This study was performed to evaluate the prevalence of abdominal aortic aneurysm (AAA) of an inpatient high-risk cohort and to estimate the co-prevalence of lower extremity arterial aneurysms.MethodsParticipants: 566 male inpatients, ≥ 65 years of age, hospitalized for suspected or known cardiopulmonary disease.Primary and secondary outcome measures: Maximal infrarenal aortic diameters using abdominal ultrasound (leading edge to leading edge method). Upon detection of an AAA (diameter ≥ 30 mm), the lower extremity arteries were examined with regard to associated aneurysms.ResultsIn 40 of 566 patients (7.1%) AAAs were detectable. Fourteen patients (2.5%) had a first diagnosis of AAA, none of which was large (> 55 mm), the remaining 26 patients were either already diagnosed (14 patients, 2.5%) or previously repaired (12 patients, 2.1%).The three most common main diagnoses at discharge were acute coronary syndrome (43.3%), congestive heart failure (32.2%), and chronic obstructive pulmonary disease (12%). The cohort showed a distinct cardiovascular risk profile comprising arterial hypertension (82.9%), diabetes mellitus (44.4%), and a history of smoking (57.6%).In multivariate analysis, three-vessel coronary artery disease (Odds ratio (OR): 4.5, 95% confidence interval (CI): 2.3–8.9, p < 0.0001) and history of smoking (OR: 3.7, CI: 1.6–8.6, p < 0.01) were positively associated with AAA, while diabetes mellitus (OR: 0.5, CI: 0.2–0.9, p = 0.0295) showed a negative association with AAA.Among the subjects with AAA, we found two large iliac and two large popliteal aneurysms.ConclusionUltrasound screening in male inpatients, hospitalized for suspected or known cardiopulmonary disease, revealed a high AAA prevalence in comparison to the present epidemiological screening programs. There was a moderate proportion of newly-screen detected AAA and additional screening of the lower extremity arteries yielded some associated aneurysms with indication for possible intervention.
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