Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system.

ABSTRACT: The 'classical' renin-angiotensin system (RAS) is a circulating system that controls blood pressure. Local/paracrine RAS, identified in a variety of tissues, including the brain, is involved in different functions and diseases, and RAS blockers are commonly used in clinical practice. A third type of RAS (intracellular/intracrine RAS) has been observed in some types of cells, including neurons. However, its role is still unknown. The present results indicate that in brain cells the intracellular RAS counteracts the intracellular superoxide/H₂O₂ and oxidative stress induced by the extracellular/paracrine angiotensin II acting on plasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number of mechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellular angiotensin, PGC-1α and IGF-1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of aged animals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrine RAS may offer better protection of cells.

SUBMITTER: Villar-Cheda B

PROVIDER: S-EPMC5636983 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Macromolecular condensation buffers intracellular water potential.

Project description:Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions1. Reciprocally, macromolecules restrict the movement of 'structured' water molecules within their hydration layers, reducing the available 'free' bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Here, within concentrated macromolecular solutions such as the cytosol, we found that modest changes in temperature greatly affect the water potential, and are counteracted by opposing changes in osmotic strength. This duality of temperature and osmotic strength enables simple manipulations of solvent thermodynamics to prevent cell death after extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength, which impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales2,3; we therefore postulated the existence of a rapid compensatory response. We find that this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically disordered proteins. The formation and dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which is consequently robustly buffered in the cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest that preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

| S-EPMC10665201 | biostudies-literature

Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5.

Project description:Soluble oligomers of amyloid beta (Abeta) play a role in the memory impairment characteristic of Alzheimer's disease. Acting as pathogenic ligands, Abeta oligomers bind to particular synapses and perturb their function, morphology, and maintenance. Events that occur shortly after oligomer binding have been investigated here in live hippocampal neurons by single particle tracking of quantum dot-labeled oligomers and synaptic proteins. Membrane-attached oligomers initially move freely, but their diffusion is hindered markedly upon accumulation at synapses. Concomitantly, individual metabotropic glutamate receptors (mGluR5) manifest strikingly reduced lateral diffusion as they become aberrantly clustered. This clustering of mGluR5 elevates intracellular calcium and causes synapse deterioration, responses prevented by an mGluR5 antagonist. As expected, clustering by artificial crosslinking also promotes synaptotoxicity. These results reveal a mechanism whereby Abeta oligomers induce the abnormal accumulation and overstabilization of a glutamate receptor, thus providing a mechanistic and molecular basis for Abeta oligomer-induced early synaptic failure.

| S-EPMC3111138 | biostudies-literature

MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling.

Project description:Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.

| S-EPMC8714172 | biostudies-literature

Macromolecular condensation buffers intracellular water potential

Project description:Optimum protein function and biochemical activity critically depends on water availability, because solvent thermodynamics drive protein folding and macromolecular interactions. Reciprocally, macromolecules restrict the movement of “structured” water molecules within their hydration layers, reducing the available “free” bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Within concentrated macromolecular solutions like the cytosol, we found modest changes in temperature greatly impact the water potential, and are counteracted by opposing changes in osmotic strength. Remarkably, this duality of temperature and osmotic strength allows simple manipulations of solvent thermodynamics to prevent cell death upon extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength that impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales, so we postulated the existence of a rapid compensatory response. We find this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically-disordered proteins. Formation or dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which in consequence is robustly buffered in the cytoplasm. Our results indicate biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

2023-09-22 | PXD044481 | Pride

Persistent deleterious effects of a deleterious Wolbachia infection.

Project description:Wolbachia are being used to reduce dengue transmission by Aedes aegypti mosquitoes around the world. To date releases have mostly involved Wolbachia strains with limited fitness effects but strains with larger fitness costs could be used to suppress mosquito populations. However, such infections are expected to evolve towards decreased deleterious effects. Here we investigate potential evolutionary changes in the wMelPop infection transferred from Drosophila melanogaster to Aedes aegypti more than ten years (~120 generations) ago. We show that most deleterious effects of this infection have persisted despite strong selection to ameliorate them. The wMelPop-PGYP infection is difficult to maintain in laboratory colonies, likely due to the persistent deleterious effects coupled with occasional maternal transmission leakage. Furthermore, female mosquitoes can be scored incorrectly as infected due to transmission of Wolbachia through mating. Infection loss in colonies was not associated with evolutionary changes in the nuclear background. These findings suggest that Wolbachia transinfections with deleterious effects may have stable phenotypes which could ensure their long-term effectiveness if released in natural populations to reduce population size.

| S-EPMC7159649 | biostudies-literature

The intracellular renin-angiotensin system: Friend or foe. Some light from the dopaminergic neurons.

Project description:The renin-angiotensin system (RAS) is one of the oldest hormone systems in vertebrate phylogeny. RAS was initially related to regulation of blood pressure and sodium and water homeostasis. However, local or paracrine RAS were later identified in many tissues, including brain, and play a major role in their physiology and pathophysiology. In addition, a major component, ACE2, is the entry receptor for SARS-CoV-2. Overactivation of tissue RAS leads several oxidative stress and inflammatory processes involved in aging-related degenerative changes. In addition, a third level of RAS, the intracellular or intracrine RAS (iRAS), with still unclear functions, has been observed. The possible interaction between the intracellular and extracellular RAS, and particularly the possible deleterious or beneficial effects of the iRAS activation are controversial. The dopaminergic system is particularly interesting to investigate the RAS as important functional interactions between dopamine and RAS have been observed in the brain and several peripheral tissues. Our recent observations in mitochondria and nucleus of dopaminergic neurons may clarify the role of the iRAS. This may be important for the developing of new therapeutic strategies, since the effects on both extracellular and intracellular RAS must be taken into account, and perhaps better understanding of COVID-19 cell mechanisms.

| S-EPMC7543790 | biostudies-literature

Extracellular and Intracellular Angiotensin II Regulate the Automaticity of Developing Cardiomyocytes <i>via</i> Different Signaling Pathways.

Project description:Angiotensin II (Ang II) plays an important role in regulating various physiological processes. However, little is known about the existence of intracellular Ang II (iAng II), whether iAng II would regulate the automaticity of early differentiating cardiomyocytes, and the underlying mechanism involved. Here, iAng II was detected by immunocytochemistry and ultra-high performance liquid chromatography combined with electrospray ionization triple quadrupole tandem mass spectrometry in mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) and neonatal rat ventricular myocytes. Expression of AT1R-YFP in mESC-CMs revealed that Ang II type 1 receptors were located on the surface membrane, while immunostaining of Ang II type 2 receptors (AT2R) revealed that AT2R were predominately located on the nucleus and the sarcoplasmic reticulum. While extracellular Ang II increased spontaneous action potentials (APs), dual patch clamping revealed that intracellular delivery of Ang II or AT2R activator C21 decreased spontaneous APs. Interestingly, iAng II was found to decrease the caffeine-induced increase in spontaneous APs and caffeine-induced calcium release, suggesting that iAng II decreased spontaneous APs via the AT2R- and ryanodine receptor-mediated pathways. This is the first study that provides evidence of the presence and function of iAng II in regulating the automaticity behavior of ESC-CMs and may therefore shed light on the role of iAng II in fate determination.

| S-EPMC8425478 | biostudies-literature

Involvement of the brain renin-angiotensin system in the effects of maternal separation

Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype Litters were randomly assigned to either a maternally non-separated or 24 hour maternally separated condition. At the time of testing, all pups from a litter were sacrificed immediately by decapitation.

2010-05-16 | E-GEOD-14687 | biostudies-arrayexpress

The microbiome buffers tadpole hosts from the deleterious effects of heat stress: a hologenomic approach to understand host-microbe interactions under warming conditions.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-30 | GSE208646 | GEO

Involvement of the brain renin-angiotensin system in the effects of maternal separation

2009-07-22 | GSE14687 | GEO