Water Homoeostasis Research Articles

Transcriptional and Post-Transcriptional Regulation of Oxytocin and Vasopressin Gene Expression by CREB3L1 and CAPRIN2.

Water homoeostasis is achieved by secretion of the peptide hormones arginine vasopressin (AVP) and oxytocin (OXT) that are synthesized by separate populations of magnocellular neurones (MCNs) in the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. To further understand the molecular mechanisms that facilitate biosynthesis of AVP and OXT by MCNs, we have explored the spatiotemporal dynamic, both mRNA and protein expression, of two genes identified by our group as being important components of the osmotic defence response: Caprin2 and Creb3l1. By RNA in situ hybridization and immunohistochemistry, we have characterized the expression of Caprin2 and Creb3l1 in MCNs in the basal state, in response to dehydration, and during rehydration in the rat. We found that Caprin2 and Creb3l1 are expressed in AVP and OXT MCNs and in response to dehydration expression increases in both MCN populations. Protein levels mirror the increase in transcript levels for both CREB3L1 and CAPRIN2. In view of increased CREB3L1 and CAPRIN2 expression in OXT neurones by dehydration, we explored OXT-specific functions for these genes. By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and Northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds to Oxt mRNA and regulates its poly(A) tail length. Moreover, in response to dehydration, Caprin2 mRNA is subjected to nuclear retention, possibly to regulate Caprin2 mRNA availability in the cytoplasm. The exploration of the spatiotemporal dynamics of Creb3l1- and Caprin2-encoded mRNAs and proteins has provided novel insights beyond the AVP-ergic system, revealing novel OXT-ergic system roles of these genes in the osmotic defence response.

Diagnostic approach to low-renin hypertension.

Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.

Improvement of hydration and epidermal barrier function in human skin by a novel compound isosorbide dicaprylate.

The study involved the synthesis of a novel derivative of caprylic acid - isosorbide dicaprylate (IDC) - and the evaluation of its potential in improving water homoeostasis and epidermal barrier function in human skin. The effect of IDC on gene expression was assayed in skin organotypic cultures by DNA microarrays. The results were then confirmed for a few key genes by quantitative PCR, immuno- and cytochemistry. Final validation of skin hydration properties was obtained by four separate clinical studies. Level of hydration was measured by corneometer either by using 2% IDC lotion alone vs placebo or in combination with 2% glycerol lotion vs 2% glycerol only. A direct comparison in skin hydration between 2% IDC and 2% glycerol lotions was also carried out. The epidermal barrier function improvement was assessed by determining changes in transepidermal water loss (TEWL) on the arms before and after treatment with 2% IDC lotion versus placebo. IDC was found to upregulate the expression of AQP3, CD44 and proteins involved in keratinocyte differentiation as well as the formation and function of stratum corneum. A direct comparison between 2% IDC versus 2% glycerol lotions revealed a three-fold advantage of IDC in providing skin hydration. Severely dry skin treated with 2% IDC in combination with 2% glycerol showed 133% improvement, whereas 35% improvement was observed with moderately dry human skin. Topical isosorbide dicaprylate favourably modulates genes involved in the maintenance of skin structure and function, resulting in superior clinical outcomes. By improving skin hydration and epidermal permeability barrier, it offers therapeutic applications in skin ageing.

Cowpea (Vigna unguiculata L. Walp.) Metabolomics: Osmoprotection as a Physiological Strategy for Drought Stress Resistance and Improved Yield.

Plants usually tolerate drought by producing organic solutes, which can either act as compatible osmolytes for maintaining turgor, or radical scavengers for protecting cellular functions. However, these two properties of organic solutes are often indistinguishable during stress progression. This study looked at individualizing properties of osmotic adjustment vs. osmoprotection in plants, using cowpea as the model species. Two cultivars were grown in well-watered soil, drought conditions, or drought followed by rewatering through fruit formation. Osmoadaptation was investigated in leaves and roots using photosynthetic traits, water homoeostasis, inorganic ions, and primary and secondary metabolites. Multifactorial analyses indicated allocation of high quantities of amino acids, sugars, and proanthocyanidins into roots, presumably linked to their role in growth and initial stress perception. Physiological and metabolic changes developed in parallel and drought/recovery responses showed a progressive acclimation of the cowpea plant to stress. Of the 88 metabolites studied, proline, galactinol, and a quercetin derivative responded the most to drought as highlighted by multivariate analyses, and their correlations with yield indicated beneficial effects. These metabolites accumulated differently in roots, but similarly in leaves, suggesting a more conservative strategy to cope with drought in the aerial parts. Changes in these compounds roughly reflected energy investment in protective mechanisms, although the ability of plants to adjust osmotically through inorganic ions uptake could not be discounted.

Genetic Analysis of the Atrial Natriuretic Peptide Gene Polymorphisms among Essential Hypertensive Patients in Malaysia.

Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about the ANP relevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms of ANP to discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently. Method. ANP gene polymorphisms (I/D and A191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls. Result. This case-control study discovered a significant association between I/D polymorphisms of ANP gene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms of ANP in EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P < 0.05). Conclusion. As a risk factor, ANP gene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing the ANP gene polymorphisms in both EH and T2DM patients among Malaysian population.

Regulation of NKCC2 splicing and phosphorylation.

Transepithelial salt transport in the thick ascending limb of Henle's loop (TAL) crucially depends on the activity of the Na/K/2Cl cotransporter NKCC2. The pharmacologic blockade of NKCC2 leads to pronounced natriuresis and diuresis, which indicate key roles for NKCC2 in renal salt retrieval. The inadequate regulation of NKCC2 and the loss of NKCC2 function are associated with the disruption of salt and water homoeostasis. This review provides a specific overview of our current knowledge with respect to the regulation of NKCC2 by differential splicing and phosphorylation. Several mechanisms have evolved to adapt NKCC2 transport to reabsorptive needs. These mechanisms include the regulation of NKCC2 gene expression, the differential splicing of the NKCC2 pre-mRNA, the membrane trafficking, and the modulation of the specific transport activity. Substantial progress has been made over the past few years in deciphering the function of kinases in the regulatory network controlling NKCC2 activity and in elucidating the underlying mechanism and the functional consequences of the regulated differential splicing of the NKCC2 pre-mRNA. NKCC2 differential splicing and phosphorylation are critically involved in the modulation of the thick ascending limb of Henle's loop reabsorptive capacity and, consequently, in salt homoeostasis, volume regulation, and blood pressure control.

Aquaporins, vasopressin, and aging: current perspectives.

Functioning of the hypothalamic-neurohypophyseal-vasopressin axis is altered in aging, and the pathway may represent a plausible target to slow the process of aging. Arginine vasopressin, a nine-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension, is central in this pathway. Vasopressin has important roles in circulatory and water homoeostasis mediated by vasopressin receptor subtypes V1a (vascular), V1b (pituitary), and V2 (vascular, renal). A dysfunction in this pathway as a result of aging can result in multiple abnormalities in several physiological systems. In addition, vasopressin plasma concentration is significantly higher in males than in females and vasopressin-mediated effects on renal and vascular targets are more pronounced in males than in females. These findings may be caused by sex differences in vasopressin secretion and action, making men more susceptible than females to diseases like hypertension, cardiovascular and chronic kidney diseases, and urolithiasis. Recently the availability of new, potent, orally active vasopressin receptor antagonists, the vaptans, has strongly increased the interest on vasopressin and its receptors as a new target for prevention of age-related diseases associated with its receptor-altered signaling. This review summarizes the recent literature in the field of vasopressin signaling in age-dependent abnormalities in kidney, cardiovascular function, and bone function.

Importance of intestinal microenvironment in development of arthritis. A systematic review.

A strong connection between spondylarthropathies and inflammatory bowel diseases (IBD) is well established. About 10-15% of IBD are associated with different forms of spondylarthritis. Arthritis can be manifested as axial, peripheral form or both. The primary functions of the gastrointestinal tract are digestion and absorption of nutrients, electrocytes and maintenance of water homoeostasis. The anatomic and functional lesions could lead to the development of IBD based on molecular mimicry and bystander effects. The mechanism of the macromolecules is uptaken may affect intestinal and extraintestinal manifestation in genetically susceptible individuals by gut-associated lymphoid tissue, the interplay between innate and adaptive immunity and the neuroendocrine network.

Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2).

The Na-K-2Cl cotransporter (NKCC2; BSC1) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL). NKCC2 facilitates ∼20-25% of the reuptake of the total filtered NaCl load. NKCC2 is therefore one of the transport proteins with the highest overall reabsorptive capacity in the kidney. Consequently, even subtle changes in NKCC2 transport activity considerably alter the renal reabsorptive capacity for NaCl and eventually lead to perturbations of the salt and water homoeostasis. In addition to facilitating the bulk reabsorption of NaCl in the TAL, NKCC2 transport activity in the macula densa cells of the TAL constitutes the initial step of the tubular-vascular communication within the juxtaglomerular apparatus (JGA); this communications allows the TAL to modulate the preglomerular resistance of the afferent arteriole and the renin secretion from the granular cells of the JGA. This review provides an overview of our current knowledge with respect to the general functions of NKCC2, the modulation of its transport activity by different regulatory mechanisms, and new developments in the pathophysiology of NKCC2-dependent renal NaCl transport.

Role of organic osmolytes in water homoeostasis in skin.

The ability to conserve water is fundamental to terrestrial life. A number of organs such as the kidney and the bladder have important roles in the regulation of body water balance. The epidermis of skin is also fundamental to this process, and it is in a constant battle to prevent loss of water to the external, dry environment. Given this important role of the epidermis as a barrier to water loss, it is perhaps surprising that many of the cellular mechanisms by which human keratinocytes achieve cell volume homoeostasis, maintain epidermal hydration and adapt to biological effects from environmental stressors such as ultraviolet radiation are poorly understood. This article reviews what is known thus far and speculates about other potential mechanisms through which skin conducts water homoeostasis, with a particular emphasis on the putative role of organic osmolytes.

Twelve-year monitoring of a patient with megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is an infantile-onset inherited disease of the brain white matter with a defect in brain ion and water homoeostasis, which leads to an abnormal brain volume regulation. Clinical features of the disease can be variable, but patients typically show early-onset macrocephaly, motor abnormalities, seizures, and almost constant late-onset mild mental deterioration. Brain magnetic resonance imaging (MRI) reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions. We describe here clinical findings and volumetric MRI and (1)H-MR spectroscopic imaging ((1)H-MRSI) data of a 12-year follow-up on a patient with MLC. The patient had only slight clinical worsening during the long follow-up. Volumetric findings showed substantially unchanged cystic volumes and mild brain atrophy rate. In addition, there was no over time increase in the volume of white matter hypointense lesions seen on FLAIR images at baseline, but the degree of hypointensity of these white matter voxels increased over 12 years. Longitudinal (1)H-MRSI examination showed long-term undetectable metabolite signals in the white matter, whereas the metabolic pattern of gray matter voxels remained unchanged over time. Results show that, in MLC, the chronic brain white matter changes resulting from the brain ion, and water homeostasis can be monitored by quantitative MRI modalities. This might be important for assessing treatment effects.

Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure

Arginine vasopressin (AVP) is a 9-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension. AVP has important roles in circulatory and water homoeostasis, which are mediated by oxytocin receptors and by AVP receptor subtypes: V(1a) (mainly vascular), V(1b) (pituitary), and V(2) (renal). Vaptans are orally and intravenously active nonpeptide vasopressin-receptor antagonists. Recently, subtype-selective nonpeptide vasopressin-receptor agonists have been developed. A selective V(1a)-receptor antagonist, relcovaptan, has shown initial positive results in the treatment of Raynaud's disease, dysmenorrhea, and tocolysis. A selective V(1b)-receptor antagonist, nelivaptan, has beneficial effects in the treatment of psychiatric disorders. Selective V2-receptor antagonists including mozavaptan, lixivaptan, satavaptan, and tolvaptan induce highly hypotonic diuresis without substantially affecting the excretion of electrolytes. A nonselective V(1a)/V(2)-receptor antagonist, conivaptan, is used in the treatment for euvolaemic or hypervolemic hyponatremia. Recent basic and clinical studies have shown that AVP-receptor antagonists, especially V2-receptor antagonists, may have therapeutic potential for heart failure. This review presents current information about AVP and its antagonists.

Urinary concentration: different ways to open and close the tap

Nephrogenic diabetes insipidus (NDI) provides an excellent model for the benefits and insights that can be gained from studying rare diseases. The discovery of underlying genes identified key molecules involved in urinary concentration, including the type 2 vasopressin receptor AVPR2 and the water channel AQP2, which constitute obvious pharmacologic targets. Subsequently developed drugs targeting AVPR2 not only provide potential benefit to some patients with NDI, but are now used for much more common clinical applications as diverse as nocturnal enuresis and heart failure. Yet, the story is still evolving: clinical observations and animal experiments continue to discover new ways to affect urinary concentration. These novel pathways can potentially be exploited for therapeutic gain. Here we review the (patho)physiology of water homoeostasis, the current status of clinical management, and potential new treatments.

THU0091 Aquaporin Expression in the Synovial Tissues of Patients with Osteoarthritis and Rheumatoid Arthritis

BackgroundAquaporins (AQPs) are usually present at the plasma membrane, where they regulate the influx and outflow of water and small molecules. They are important for the regulation of water homoeostasis...

Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study

Mutant mouse models suggest that the chloride channel ClC-2 has functions in ion and water homoeostasis, but this has not been confirmed in human beings. We aimed to define novel disorders characterised by distinct patterns of MRI abnormalities in patients with leukoencephalopathies of unknown origin, and to identify the genes mutated in these disorders. We were specifically interested in leukoencephalopathies characterised by white matter oedema, suggesting a defect in ion and water homoeostasis. In this observational analytical study, we recruited patients with leukoencephalopathies characterised by MRI signal abnormalities in the posterior limbs of the internal capsules, midbrain cerebral peduncles, and middle cerebellar peduncles from our databases of patients with leukoencephalopathies of unknown origin. We used exome sequencing to identify the gene involved. We screened the candidate gene in additional patients by Sanger sequencing and mRNA analysis, and investigated the functional effects of the mutations. We assessed the localisation of ClC-2 with immunohistochemistry and electron microscopy in post-mortem human brains of individuals without neurological disorders. Seven patients met our inclusion criteria, three with adult-onset disease and four with childhood-onset disease. We identified homozygous or compound-heterozygous mutations in CLCN2 in three adult and three paediatric patients. We found evidence that the CLCN2 mutations result in loss of function of ClC-2. The remaining paediatric patient had an X-linked family history and a mutation in GJB1, encoding connexin 32. Clinical features were variable and included cerebellar ataxia, spasticity, chorioretinopathy with visual field defects, optic neuropathy, cognitive defects, and headaches. MRI showed restricted diffusion suggesting myelin vacuolation that was confined to the specified white matter structures in adult patients, and more diffusely involved the brain white matter in paediatric patients. We detected ClC-2 in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells. Our observations substantiate the concept that ClC-2 is involved in brain ion and water homoeostasis. Autosomal-recessive CLCN2 mutations cause a leukoencephalopathy that belongs to an emerging group of disorders affecting brain ion and water homoeostasis and characterised by intramyelinic oedema. European Leukodystrophies Association, INSERM and Assistance Publique-Hôpitaux de Paris, Dutch Organisation for Scientific Research (ZonMw), E-Rare, Hersenstichting, Optimix Foundation for Scientific Research, Myelin Disorders Bioregistry Project, National Institute of Neurological Disorders and Stroke, and Genetic and Epigenetic Networks in Cognitive Dysfunction (GENCODYS) Project (funded by the European Union Framework Programme 7).

Aquaporins 6-12 in the human eye

Aquaporins (AQPs) are widely expressed and have diverse distribution patterns in the eye. AQPs 0-5 have been localized at the cellular level in human eyes. We investigated the presence of the more recently discovered AQPs 6-12 in the human eye. RT-PCR was performed on fresh tissue from two human eyes divided into the cornea, corneal limbus, ciliary body and iris, lens, choroid, optic nerve, retina and sclera. Each structure was examined to detect the mRNA of AQPs 6-12. Twenty-one human eyes were examined using immunohistochemical and immunofluorescence techniques to determine the topographical localization of AQPs 6-12. mRNA transcripts of AQP7, AQP9 and AQP11 were found in the ciliary body, corneo-limbal tissue, optic nerve, retina and sclera. AQP9 and AQP11 mRNA was also detected in the choroid. No mRNA of AQP6, AQP8, AQP10 or AQP12 was detected. Anti-AQP7 immunolabelling was detected in the corneal epithelium, corneal endothelium, trabecular meshwork endothelium, ciliary epithelia, lens epithelium, the inner and outer limiting membrane of the retina, the retinal pigment epithelium and the capillary endothelium of all parts of the eye. AQP9 immunolabelling was detected in the nonpigmented ciliary epithelium and retinal ganglion cells. AQP11 immunolabelling was detected in the corneo-limbal epithelium, nonpigmented ciliary epithelium and inner limiting membrane of the retina. Selective expression of AQP7, AQP9 and AQP11 was found within various structures of the human eye. The detection of these aquaporins in the eye implies a role that may be related not only to water transport but also to the transport of glycerol, lactate and ammonia, with importance for metabolism, especially in the retina.

Carbamazepine affects water and electrolyte homoeostasis in rat--similarities and differences to vasopressin antagonism

Carbamazepine (CBZ) is a drug widely used in the therapy of epilepsy and mood disorders. One frequently observed side effect is hyponatraemia. The role of vasopressin in hyponatraemic action of CBZ is discussed controversially. In this study, we tested the influence of CBZ on water and salt homoeostasis in rat under different hydration states and under vasopressin 2 receptor (V2R) antagonism by satavaptan to elucidate the renal and vasopressin independent action of CBZ. CBZ-treated rats were investigated on metabolic cages after (i) 6 day with ad libitum fluid intake, (ii) moderate water load and (iii) water restriction. The effect of satavaptan was tested in clearance experiments under continuous saline infusion in anaesthetized rats after CBZ pretreatment. Compared to controls, CBZ induced a higher urinary flow rate which was most pronounced (20-fold) after water load and significantly elevated (2-fold) after 10-h water restriction. In addition, CBZ consistently increased renal sodium loss but failed to decrease plasma sodium concentration. In the presence of satavaptan, urinary flow and natriuresis were further increased by CBZ, while there was no differential effect on urea excretion and anion gap. At the investigated dose (50 mg/kg body weight), CBZ did not induce hyponatraemia or antidiuresis in the rat. However, depending on the hydration state, it induced an increased water and electrolyte loss. Its enhanced influence on urinary flow and natriuresis in the presence of satavaptan suggests additional renal targets for CBZ, independent of vasopressin signalling.

Adult murine CNS stem cells express aquaporin channels

Fluid homoeostasis is of critical importance in many functions of the CNS (central nervous system) as indicated by the fact that dysregulation of cell volume underlies clinical conditions such as brain oedema and hypoxia. Water balance is also important during neurogenesis as neural stem cells move considerable amounts of water into or out of the cell to rapidly change their volume during differentiation. Consistent with the relevance of water transport in CNS, multiple AQP (aquaporin) water channels have been recognized and partially characterized in brain cell function. However, the presence and distribution of AQPs in CNS stem cells has not yet been assessed. In the present study, we investigate the expression and subcellular localization of AQPs in murine ANSCs (adult neural stem cells). Considerable AQP8 mRNAs were found in ANSCs where, as expected, the transcript of two additional AQPs, AQP4 and AQP9, was also detected. Immunoblotting with subcellular membrane fractions of ANSCs showed predominant expression of AQP8 in the mitochondria-enriched fraction. This result was consistent with the spotted immunoreactivity profile encountered within the ANSCs by confocal immunofluorescence. AQP8 may have a role in mitochondrial volume regulation during ANSC differentiation. Recognition of AQPs in ANSCs is a step forward in our knowledge of water homoeostasis in the CNS and provides useful information for the purposes of stem cell technology.

Trafficking mechanism of water channel aquaporin‐2

Targeted positioning of the water channel AQP2 (aquaporin-2) strictly regulates body water homoeostasis. Trafficking of AQP2 to the apical membrane is critical for the reabsorption of water in renal collecting ducts. In addition to the cAMP-mediated effect of vasopressin on AQP2 trafficking to the apical membrane, other signalling cascades can also induce this sorting. Recently, AQP2-binding proteins which could regulate this trafficking have been discovered; SPA-1 (signal-induced proliferation-associated gene-1), a GAP (GTPase-activating protein) for Rap1, and the cytoskeletal protein actin. This review summarizes recent advances related to the trafficking mechanisms of AQP2.

Central role of the AT(1)-receptor in atherosclerosis.

The renin-angiotensin system plays a major role in the pathogenesis of atherosclerosis. Most known effects of angiotensin II are mediated via activation of the AT(1)-receptor, which is in turn influenced to a great degree by levels of expression of the AT(1)-receptor. AT(1)-receptor activation is not only involved in vasoconstriction, water and salt homoeostasis and control of other neurohumoral systems, but also induces reactive oxygen species production, cellular hypertrophy and hyperplasia and apoptosis. Expression of this G-protein-coupled receptor is regulated by multiple factors. Among other conditions, oestrogen deficiency and hypercholesterolaemia increase AT(1)-receptor expression. Experimental data suggest that this augments the actions of angiotensin II, contributes to endothelial dysfunction, increases vascular production of reactive oxygen species, and via these mechanisms promotes atherosclerosis. Because of this, AT(1)-receptor regulation is likely to be critical in the development and progression of vascular lesions. Interventional studies demonstrated that ACE inhibitors which reduce AT(1)-receptor activation, improve endothelial dysfunction and inhibit onset and progression of atherosclerosis. The more specific AT(1)-receptor antagonists have also been shown to decrease blood pressure, protect renal function and to improve endothelial function. Thus, there is compelling evidence that AT(1)-receptor activation participates in the pathogenesis of atherosclerosis, and more importantly, that treatment regimens aiming at inhibition of AT(1)-receptor activation are promising anti-atherosclerotic therapeutic options.