Angiotensinogen: Hormonal regulation and relative importance in the generation of angiotensin II

Angiotensinogen: Hormonal regulation and relative importance in the generation of angiotensin II. The production of angiotensinogen is controlled mainly by hormones that affect the concentration of its mRNA in tissues. Accordingly, hormones that act upon gene transcription play a prominent role. However, other factors may modulate the transcriptional effects of hormones, and these should be considered to appreciate the final effects of hormones on the secretion of angiotensinogen. The most important role played by hormones in the regulation of angiotensinogen may be to maintain its production in the face of rapid consumption by high levels of renin. However, elevated levels of angiotensinogen may become a risk factor in situations where the normal feedback regulation of renin does not operate normally. Finally, the synthesis of angiotensinogen in tissues may be regulated differentially than that in liver, although the exact importance of these observations is still poorly understood

Evidence for intracellular generation of angiotensin II in rat juxtaglomerular cells

AbstractThe formation of the vasoactive peptide angiotensin II (AII) is dependent on the sequential action of two enzymes, renin and angiotensin converting enzyme (ACE), on the substrate angiotensinogen. Although the renin-producing cells of the kidney do not express angiotensinogen, they contain large amounts of AII in the same storage granules that contain renin. When renin expression is suppressed in these cells, AII also disappears. In the current study, we have tested whether the renin-associated disappearance of AII in renal juxtaglomerular (JG) cells is due to a renin-dependent down-regulation of granule biosynthesis and whether receptor-mediated internalization of AII could account for its concentration in these cells. Our results support a model whereby AII peptides are generated within JG cells, presumably by a mechanism which involves the action of endogenous renin on internalized, exogenous angiotensinogen

Importance of randomization in microarray experimental designs with Illumina platforms

Measurements of gene expression from microarray experiments are highly dependent on experimental design. Systematic noise can be introduced into the data at numerous steps. On Illumina BeadChips, multiple samples are assayed in an ordered series of arrays. Two experiments were performed using the same samples but different hybridization designs. An experiment confounding genotype with BeadChip and treatment with array position was compared to another experiment in which these factors were randomized to BeadChip and array position. An ordinal effect of array position on intensity values was observed in both experiments. We demonstrate that there is increased rate of false-positive results in the confounded design and that attempts to correct for confounded effects by statistical modeling reduce power of detection for true differential expression. Simple analysis models without post hoc corrections provide the best results possible for a given experimental design. Normalization improved differential expression testing in both experiments but randomization was the most important factor for establishing accurate results. We conclude that lack of randomization cannot be corrected by normalization or by analytical methods. Proper randomization is essential for successful microarray experiments

Network statistics of genetically-driven gene co-expression modules in mouse crosses

In biology, networks are used in different contexts as ways to represent relationships between entities, such as for instance interactions between genes, proteins or metabolites. Despite progress in the analysis of such networks and their potential to better understand the collective impact of genes on complex traits, one remaining challenge is to establish the biologic validity of gene co-expression networks and to determine what governs their organization. We used WGCNA to construct and analyze seven gene expression datasets from several tissues of mouse recombinant inbred strains (RIS). For six out of the 7 networks, we found that linkage to module QTLs (mQTLs) could be established for 29.3% of gene co-expression modules detected in the several mouse RIS. For about 74.6% of such genetically-linked modules, the mQTL was on the same chromosome as the one contributing most genes to the module, with genes originating from that chromosome showing higher connectivity than other genes in the modules. Such modules (that we considered as genetically-driven) had network statistic properties (density, centralization and heterogeneity) that set them apart from other modules in the network. Altogether, a sizeable portion of gene co-expression modules detected in mouse RIS panels had genetic determinants as their main organizing principle. In addition to providing a biologic interpretation validation for these modules, these genetic determinants imparted on them particular properties that set them apart from other modules in the network, to the point that they can be predicted to a large extent on the basis of their network statistics

Protective Effects of Aspirin from Cardiac Hypertrophy and Oxidative Stress in Cardiomyopathic Hamsters

Objective. To evaluate the capacity of chronic ASA therapy to prevent cardiac alterations and increased oxidative stress in cardiomyopathic hamsters. Methods and Results. Male Syrian cardiomyopathic and age-matched inbred control hamsters received ASA orally from the age of 60 days. Animals were sacrificed at the age of 150, 250, and 350 days to evaluate the time course of cardiac hypertrophy and cardiovascular tissue superoxide anion (O2-) production. At the age of 150 days, the ventricular weight over body weight ratio, resting heart rate, and cardiovascular O2- production were much higher in cardiomyopathic hamsters than those in control. At the age of 250 days, in addition to the continual deterioration of these parameters with age, the blood pressure started to fall and the signs of heart failure appeared. In these cardiomyopathic hamsters, chronic ASA treatment (a) completely prevented elevated O2- production and the NAD(P)H oxidase activity, (b) significantly slowed down the development of the cardiac hypertrophy and fibrosis. Conclusions. Chronic ASA treatment significantly prevents the deterioration of cardiac function and structure as well as the increased oxidative stress in the cardiomyopathic hamster. Our findings suggest that ASA presents a therapeutic potential to prevent cardiac dysfunction

Dual linkage of a locus to left ventricular mass and a cardiac gene co-expression network driven by a chromosome domain

We have previously reported Lvm1 as a quantitative trait locus (QTL) on chromosome 13 (chr13) that links to cardiac left ventricular mass (LVM) in a panel of AxB/BxA mouse recombinant inbred strains (RIS). When performing a gene expression QTL (eQTL) analysis, we detected 33 cis-eQTLs that correlated with LVM. Among the latter, a group of 8 cis-eQTLs clustered in a genomic region smaller than 6 Mb and surrounding the Lvm1 peak on chr13. Co-variant analysis indicated that all 8 genes correlated with the phenotype in a causal rather than a reactive fashion, a finding that (despite its functional interest) did not provide grounds to prioritize any of these candidate genes. As a complementary approach, we performed weighted gene co-expression network analysis, which allowed us to detect 49 modules of highly connected genes. The module that correlated best with LVM: 1) showed linkage to a module QTL whose boundaries matched closely those of the phenotypic Lvm1 QTL on chr13; 2) harbored a disproportionately high proportion of genes originating from a small genomic region on chromosome 13 (including the 8 previously detected cis-eQTL genes); 3) contained genes that, beyond their individual level of expression, correlated with LVM as a function of their inter-connectivity; and 4) showed increased abundance of polymorphic insertion-deletion elements in the same region. Taken together, these data suggest that a domain on chromosome 13 constitutes the biologic principle responsible for the organization and linkage of the gene co-expression module, and indicate a mechanism whereby genetic variants within chromosome domains may associate to phenotypic changes via coordinate changes in the expression of several genes. One other possible implication of these findings is that candidate genes to consider as contributors to a particular phenotype should extend further than those that are closest to the QTL peak