Angiotensin Receptor Subtypes Research Articles

Angiotensin II increases the firing activity of pallidal neurons and participates in motor control in rats.

The globus pallidus has emerged as a crucial node in the basal ganglia motor control circuit under both healthy and parkinsonian states. Previous studies have shown that angiotensin II (Ang II) and angiotensin subtype 1 receptor (AT1R) are closely related to Parkinson's disease (PD). Recent morphological study revealed the expression of AT1R in the globus pallidus of mice. To investigate the functions of Ang II/AT1R on the globus pallidus neurons of both normal and parkinsonian rats, electrophysiological recordings and behavioral tests were performed in the present study. Electrophysiological recordings showed that exogenous and endogenous Ang II mainly excited the globus pallidus neurons through AT1R. Behavioral tests further demonstrated that unilateral microinjection of Ang II into the globus pallidus induced significantly contralateral-biased swing in elevated body swing test (EBST), and bilateral microinjection of Ang II into the globus pallidus alleviated catalepsy and akinesia caused by haloperidol. AT1R was involved in Ang II-induced behavioral effects. Immunostaining showed that AT1R was expressed in the globus pallidus of rats. On the basis of the present findings, we concluded that pallidal Ang II/AT1R alleviated parkinsonian motor deficits through activating globus pallidus neurons, which will provide a rationale for further investigations into the potential of Ang II in the treatment of motor disorders originating from the basal ganglia.

Evidence of Renin–Angiotensin System Receptors in Deep Fascia: A Role in Extracellular Matrix Remodeling and Fibrogenesis?

Recent studies have shown that fascial fibroblasts are sensitive to different stimuli (biochemical or biophysical), promoting extracellular matrix remodeling, as well as synthetic activity. Moreover, the extensive literature on the renin–angiotensin system (RAS) reported its involvement in tissue remodeling. This study aimed to investigate the presence of RAS components in the deep fascia. Thoracolumbar fascia specimens were collected from 13 patients (age range: 25–75 years; seven males and five females) who had undergone elective spinal surgical procedures at the Orthopedic Clinic of the University of Padova. Gene expression analysis was performed to investigate the expression of Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), MAS receptor (MasR), angiotensinogen, angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme 1 (ACE1). AT1R and ACE2 were also measured with immunoblot. AT1R was the most expressed angiotensin receptor subtype (300.2 ± 317 copies/25 ng of mRNA), followed by MasR (37.1 ± 39.56 copies/25 ng of mRNA) and AT2R (147 ± 122 copies/25 ng of mRNA). The amounts of angiotensinogen, ACE1 and ACE2 were hardly detectable. These findings demonstrate that RAS system receptors are present in the deep fascia, with a greater expression of AT1R, suggesting their involvement in fascial remodeling and fibrogenesis.

Angiotensin Receptor Blockers Associated with Improved Breast Cancer Survival-A Nationwide Cohort Study from Finland.

Breast cancer incidence has been associated with hypertension, which might worsen disease prognosis, but few nationwide studies have investigated the association between antihypertensive drug use and breast cancer prognosis. A cohort of 73,170 women diagnosed with breast cancer during 1995-2013 identified from the Finnish Cancer Registry was combined with information on antihypertensive drug use during the same time period from a national prescription database. Antihypertensive drugs were analyzed in groups categorized by mechanism of action. Usage of antihypertensive drugs, statins, antidiabetic, and anticoagulative drugs was analyzed as time-dependent exposure to model for simultaneous use of multiple drug groups. Influence of protopathic bias was evaluated in lag-time analyses. In prediagnostic use, only angiotensin receptor (ATR)-blockers were associated with decreased risk of breast cancer death as compared with nonusers (HR: 0.76, 95% confidence interval, CI: 0.69-0.82), and there was an inverse association with cumulative dose of use. Postdiagnostic use of ATR-blockers, angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, and calcium-channel blockers was dose dependently associated with better breast cancer survival compared with nonusers. The risk decrease was strongest for ATR-blockers (HR: 0.69, 95% CI: 0.63-0.75) and remained for exposures occurring up to 3 years earlier. Only ATR-blockers were associated with improved breast cancer survival in both prediagnostic and postdiagnostic use. The association was dose dependent and supported by a biological rationale as a causal explanation. In postdiagnostic use, similar reduction was found also for other antihypertensives, supporting a prognostic role of hypertension control. Inhibition of angiotensin receptor subtype 1 (AT1) could be a promising novel way to affect breast cancer progression.

Brain Renin-Angiotensin System at the Intersect of Physical and Cognitive Frailty.

The renin–angiotensin system (RAS) was initially considered to be part of the endocrine system regulating water and electrolyte balance, systemic vascular resistance, blood pressure, and cardiovascular homeostasis. It was later discovered that intracrine and local forms of RAS exist in the brain apart from the endocrine RAS. This brain-specific RAS plays essential roles in brain homeostasis by acting mainly through four angiotensin receptor subtypes; AT1R, AT2R, MasR, and AT4R. These receptors have opposing effects; AT1R promotes vasoconstriction, proliferation, inflammation, and oxidative stress while AT2R and MasR counteract the effects of AT1R. AT4R is critical for dopamine and acetylcholine release and mediates learning and memory consolidation. Consequently, aging-associated dysregulation of the angiotensin receptor subtypes may lead to adverse clinical outcomes such as Alzheimer’s disease and frailty via excessive oxidative stress, neuroinflammation, endothelial dysfunction, microglial polarization, and alterations in neurotransmitter secretion. In this article, we review the brain RAS from this standpoint. After discussing the functions of individual brain RAS components and their intracellular and intracranial locations, we focus on the relationships among brain RAS, aging, frailty, and specific neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and vascular cognitive impairment, through oxidative stress, neuroinflammation, and vascular dysfunction. Finally, we discuss the effects of RAS-modulating drugs on the brain RAS and their use in novel treatment approaches.

Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson's Disease.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons from the substantia nigra (SN) that project to the dorsal striatum (caudate-putamen). To better understand the molecular mechanisms underlying PD, we performed combined lipid profiling and RNA sequencing of SN and putamen samples from PD patients and age-matched controls. SN lipid analysis pointed to a neuroinflammatory component and included elevated levels of the endosomal lipid Bis (Monoacylglycero)Phosphate 42:8, while two of the three depleted putamen lipids were saturated sphingomyelin species. Remarkably, we observed gender-related differences in the SN and putamen lipid profiles. Transcriptome analysis revealed that the top-enriched pathways among the 354 differentially expressed genes (DEGs) in the SN were “protein folding” and “neurotransmitter transport”, and among the 261 DEGs from putamen “synapse organization”. Furthermore, we identified pathways, e.g., “glutamate signaling”, and genes, encoding, e.g., an angiotensin receptor subtype or a proprotein convertase, that have not been previously linked to PD. The identification of 33 genes that were common among the SN and putamen DEGs, which included the α-synuclein paralog β-synuclein, may contribute to the understanding of general PD mechanisms. Thus, our proof-of-concept data highlights new genes, pathways and lipids that have not been explored before in the context of PD.

Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.

Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation.

To review recent data that suggest opposing effects of brain angiotensin type-1 (AT1R) and type-2 (AT2R) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of AT1R and anti-hypertensive and anti-inflammatory actions of AT2R. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain AT1R and AT2R, both of which are expressed in or adjacent to brain regions that control BP. Activation of AT1R within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that AT1R and AT2R have opposing actions on BP suggests that AT1R and AT2R may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain AT1R and AT2R mediate neuroinflammatory responses remain unclear. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.

Stimulation of Angiotensin II Receptor 2 Preserves Cognitive Function Post Stroke and is Associated with an Enhanced Cerebral Vascular Density in Female Rats.

Angiotensin signaling is known to be sexually dimorphic and although a well‐studied target for intervention in stroke and cognitive impairment in males, studies in females are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of stimulation of the angiotensin receptor subtype 2 (AT2R) with compound 21 (C21) on the development of post‐stroke cognitive impairment after experimental ischemic stroke. Ovariectomized (OVX), spontaneously hypertensive rats (SHRs) were subjected to 1 hour of middle cerebral artery occlusion (MCAO) using the suture model. At 24 hours, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. In a separate cohort of female SHRs, mean arterial pressure (MAP) was monitored continuously using telemetry units (Data Sciences International, St. Paul, MN). Rats were then randomized to the following treatment groups: low dose C21 (0.216 mg/kg/day, SC, Alzet Pump, Cupertino, CA), high dose C21 (0.432 mg/kg/day, SC), or surgical sham control. MAP was monitored for an additional 2 weeks. Outcomes measured were sensorimotor and cognitive function, brain structure by MRI and vascular architecture by microCT Angiography. Compound 21 preserved cognitive function, specifically spatial memory, without a significant effect on sensorimotor function or infarct size as measured by MRI. Interestingly, animals treated with C21 had a 2‐fold increase in vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. Neither low nor high dose C21 affected MAP. In conclusion, C21 prevented cognitive impairment after stroke independent of changes in MAP, likely through a mechanism involving vascular protection and restoration.Support or Funding InformationR01NS104573 to AE and SCF. Jowdy Professorship to SCF Data are mean ± SEM Saline C21 MAP (mmHg) 128±2 Low dose: 136±54# High Dose: 134±4# Bederson at Randomization 2.9 ± 0.4 2.5 ± 0.42# Bederson at 6 weeks 5 ± 0.33 N=10 5.87 ± 0.47 N =8# Infarct Size by MRI (% contralateral side) 18.74 ±1.82 N=6 14.76 ± 4.16 N=5# Sham Stroked Saline C21 Saline C21 Passive Avoidance (Latency in seconds) 276 ± 8.9, N=5 286.3 ± 3.8, N=4 91.83 ± 50.14, N=6 279 ± 5.8a, N=5 Object Placement Test (% time with moved object) 55.06 ± 4.0 N=9 45.27 ± 4.0 N=8 41.77 ± 3.72 N=10 71.6 ± 6.9a N8 MicroCT Angiography Vessel Volume/Total Volume 0.45 ± 0.08 N=4 0.51 ± 0.07 N=4 0.29 ± 0.06 N=4 0.81 ± 0.09a N=3 Vessel Number 0.04±0.007 0.04 ± 0.006 0.03 ± 0.007 0.08 ± 0.011a Vessel Thickness 0.1002± 0.007 0.1101± 0.007 0.0902± 0.007 0.0948± 0.011# Vessel Separation 1.59± 0.03 1.48 ± 0.16 1.91± 0.14 1.37± 0.12b #p>0.05 vs saline, apost‐hoc Bonferoni p< 0.01 vs stroke saline, bpost‐hoc Bonferoni p<0.05 vs stroke saline.

Exercise training attenuates angiotensin II-induced vasoconstriction in the aorta of normotensive but not hypertensive rats.

What is the central question of this study? What are the effects of exercise on Ang II-induced vasoconstriction in aortas of normotensive rats and how do these effects occur in two-kidney-one-clip hypertensive animals? What is the main finding and its importance? In two-kidney rats, exercise training improves the Ang II-induced vasoconstriction by endothelium-derived NO released through AT2 R activation. This effect of exercise training on the Ang II-induced vasoconstriction is blunted in two-kidney-one-clip hypertensive animals, possibly as a consequence of oxidative stress. This study investigated the effects of both acute exercise and training on the Ang II-induced vasoconstriction in aorta of normotensive (two-kidney; 2K) and two-kidney-one-clip (2K1C) hypertensive rats, focusing on endothelial mechanisms related to nitric oxide (NO) and prostanoids. Aorta rings of 2K and 2K1C male Wistar rats, sedentary and trained, killed at rest and after acute exercise, were challenged with Ang II in either the absence or the presence of PD 123,319, a selective angiotensin receptor subtype 2 (AT2 R) antagonist; Nω -nitro-l-arginine methyl ester (l-NAME), a non-selective inhibitor of nitric oxide synthase; indomethacin, a non-selective inhibitor of cyclooxygenase; or Tiron, an analogue of superoxide dismutase. Aortas of sedentary and trained animals studied at rest were also submitted to histomorphometric analysis. Exercise training reduced the Ang II-induced vasoconstriction in aorta of 2K but not of 2K1C animals. This reduction of Ang II response in aortas of 2K animals was not found after endothelial removal or treatment with PD 123,319 or l-NAME. These results suggest that exercise training improves the modulation of Ang II-induced vasoconstriction in aorta of 2K animals, by endothelium-derived NO released due to the activation of AT2 R. No exercise-induced change of Ang II response occurred in 2K1C animals, except in the presence of Tiron, which was evidence for reduction of such responses only in resting trained 2K1C animals. In 2K1C animals, NO modulation of Ang II-induced vasoconstriction might be suppressed by local oxidative stress. Moreover, exercise training slightly reduced the media layer thickness in the aortas of the 2K1C, but not 2K animals, which may indicate cardiovascular protection of these animals.

Angiotensin receptor subtypes regulate adipose tissue renewal and remodelling.

Obesity is often associated with high systemic and local renin-angiotensin system (RAS) activity in adipose tissue. Adipose-derived mesenchymal stem/stromal cells (ADSCs), responsible for adipose tissue growth upon high-fat diet, express multiple angiotensin II receptor isoforms, including angiotensin II type 1 receptor (AT1 R), angiotensin II type 2 receptor (AT2 R), Mas and Mas-related G protein-coupled receptor D. Although AT1 R is expressed on most ADSCs, other angiotensin receptors are co-expressed on a small subpopulation of the cells, a phenomenon that results in a complex response pattern. Following AT1 R activation, the effects are transient due to rapid receptor internalisation. This short-lived effect can be prevented by heteromerisation with AT2 R, a particularly important strategy for the regulation of ADSC differentiation and secretory activity. Heteromeric AT2 R might be especially important for the generation of thermogenic beige adipocytes. This review summarises current data regarding the regulation of adipose tissue renewal and particularly ADSC adipogenic differentiation and secretory activity by RAS, with an emphasis on AT2 R and its effects. We reveal a new scheme that implicates AT2 R into the regulation of ADSC hormonal sensitivity.

Methylation-reprogrammed AGTR1 results in increased vasoconstriction by angiotensin II in human umbilical cord vessel following in vitro fertilization-embryo transfer

AimsAssisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. Materials and methodsHuman umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. Key findingsIn IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SignificanceThe hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.

Sex Differences in the Central and Peripheral Manifestations of Heart Failure in Rats

Heart failure (HF) is a leading cause of morbidity and mortality for both men and women. Increased sympathetic nerve activity (SNA) is a hallmark of HF and correlates with poor prognosis. We and others have demonstrated that neuroinflammation and renin‐angiotensin system activity are elevated in the cardiovascular‐related regions of the brain in HF, contributing to SNA and the progression of HF. However, most studies that have examined these sympathoexcitatory mediators in the brain in HF have been performed in male animals. The goal of this study was to determine whether sex differences exist in neuroinflammation and renin‐angiotensin system activity in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular‐related center of the brain that regulates SNA and extracellular fluid volume, in rats with HF. Male and female SD rats at ~13 weeks of age underwent coronary artery ligation (CL) to induce HF and were euthanized for anatomical and molecular studies 4 weeks later. Age‐matched male and female rats served as controls. There were no differences between male and female rats in echocardiography‐defined ischemic zone or left ventricular ejection fraction at 24 hours and at 4 weeks after CL. Female rats had lower body weight than male rats, but there was no difference in body weight between HF and control rats in either sex. At 4 weeks, lung weight was similar but right ventricular (RV) and left ventricular (LV) weights were smaller in female control than male control rats. Compared with their respective controls, male HF but not female HF rats had increases in lung weight/tibial length and RV weight/tibial length. There was no difference in LV dP/dtmax and LV end‐diastolic pressure between male and female controls. LV dP/dtmax was decreased in both male HF rats and female HF rats, but male HF rats had a lower dP/dtmax. Compared with their respective control rats, male but not female HF rats had increased LV end‐diastolic pressure. In the PVN, mRNA for tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), angiotensin receptor subtype 1a receptor (AT1aR) and estrogen receptors α and β (ER‐α, ER‐β) was similar in male and female controls. mRNA for G protein‐coupled estrogen receptor (GPER) was higher and mRNA for arginine vasopressin (AVP) was lower in female control than male control rats. Both male HF and female HF rats had increases in TNF‐α, IL‐1β, AT1aR and AVP mRNA in the PVN, compared with their respective controls, but the levels were higher in the male HF rats. ER‐α and ER‐β mRNA was decreased and GPER mRNA was unchanged in male HF and female HF rats, compared with respective controls. There was no difference in ERK1/2 activity in the PVN between male and female control rats, and ERK1/2 activity in the PVN was equally increased in both male and female HF rats. Plasma angiotensin II, AVP and norepinephrine levels were similar in male and female control rats. The plasma levels of these humoral factors were higher in HF rats in either sex, but the AVP and norepinephrine levels were greater in male HF rats. These preliminary results suggest that female rats with HF following CL have less central neural inflammation and renin‐angiotensin system activity, less peripheral sympathetic and vasopressinergic activity and less hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. The mechanisms responsible for these sex differences remain to be determined.Support or Funding InformationSupported by NIH HLR01HL136149 and R01HL073986.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabolic Syndrome Induces Over Expression of the Human AT1R: A Haplotype-Dependent Effect With Implications on Cardio-Renal Function.

The transcriptional regulation of the human angiotensin receptor subtype 1 (AT1R) gene in pathophysiologies, like the metabolic syndrome, is poorly understood. The human AT1R gene has polymorphisms in its promoter that can be arranged in 2 haplotypes. Variants -810T, -713T, -214A, and -153A always occur together (Hap-I) and variants -810A, -713G, -214C, and -153G form Hap-II. We have hypothesized that high fat diet will alter cellular transcriptional milieu and increase hAT1R gene expression in a haplotype-dependent manner. This will set up an AT1R-mediated feed-forward loop promoting inflammation, oxidative stress, and hypertension in Hap-I mice. Since Hap-I of the human AT1R gene is associated with hypertension in Caucasians, we generated transgenic (TG) mice with Hap-I and Hap-II and studied the physiological significance of high fat diet (HFD) on haplotype specific gene expression. Animals were fed with HFD for 20 weeks followed by blood pressure (BP) analysis and collection of their tissues for molecular and biochemical studies. After HFD treatment, as compared to Hap-II, TG mice with Hap-I show increased expression of hAT1R gene and higher BP; suppression of antioxidant defenses (HO1, SOD1) and increased expression of IL-6, TNFα, IL-1β, NOX1. In vivo ChIP assay has shown that transcription factors CEBPβ, STAT3, and USF bind more strongly to the chromatin obtained from Hap-I TG mice. Taken together, our results suggest, that after HFD treatment, as compared to Hap-II, the TG mice with Hap-I overexpress the AT1R gene due to the stronger transcriptional activity, thus resulting in an increase in their BP.

Prognostic significance of USP33 in advanced colorectal cancer patients: new insights into β-arrestin-dependent ERK signaling.

Patients with liver metastases of colorectal cancer (CRCLM) have a poorer prognosis compared to colorectal cancer (CRC) patients in local stage. Evaluating the recurrence and overall survival of advanced patients is critical in improving disease treatment and clinical outcome. Here we investigated the expression pattern of USP33, a deubiquitinating enzyme, in both primary CRC tissues and liver metastases tissues. Univariate and multivariate analyses identified that low expression of USP33 in CRCLM tissues indicated high recurrence risk and poor overall prognosis. Overexpression of USP33 can significantly inhibit cell proliferation, migration, and invasion. On the other hand, USP33 knock-down promoted cell proliferation and invasion under SDF-1 stimulation; whereas dynasore (an internalization inhibitor) pretreatment in USP33 silencing cells showed a distinct antipromoting effect, revealing the participation of CXCR4 internalization in regulating tumor progress. Further results verified that USP33 can deubiquitinate β-arrestin2, subsequently block the internalization of SDF-1-stimulated CXCR4, and disrupt β-arrestin-dependent ERK activation. The existence and functions of β-arrestin-dependent signaling have been previously determined in several Gs-coupled receptors, such as β2-adrenergic receptor and angiotensin receptor subtype 1a; however, little is known about this in Gi-coupled receptors. Our study not only established USP33 as a novel prognosis biomarker in advanced CRCLM patients, but also highlighted the significance of β-arrestin-dependent ERK signaling in cancer development.

Mechanisms of Cachexia in Chronic Disease States

Sarcopenia and cachexia are muscle wasting syndromes associated with aging and with many chronic diseases, such as congestive heart failure (CHF), diabetes, cancer, chronic obstructive pulmonary disease and chronic kidney disease (CKD). While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme inhibitor treatment improves weight loss. It was found that Ang II infusion in rodents leads to skeletal muscle wasting. Ang II increases cytokines and circulating hormones, such as tumor necrosis factor-α, interleukin-6, serum amyloid-A and glucocorticoids, which regulate muscle protein synthesis and degradation. Ang II–induced muscle wasting is caused by alterations in insulin-like growth factor-1 signaling, enhanced muscle protein breakdown via the ubiquitin-proteasome system and decreased appetite resulting from the downregulation of hypothalamic orexigenic neuropeptides, such as Npy and orexin. Ang II also inhibits 5′ adenosine monophosphate–activated protein kinase activity and disrupts normal energy balance via the activation of 5′ adenosine monophosphate–activated protein kinase phosphatase PP2Cα. Furthermore, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to lowered muscle regenerative capacity. Distinct satellite cell angiotensin receptor subtypes have different effects on different stages of differentiation and are critical for the regulation of muscle regeneration. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states, and it is a promising target for the treatment of muscle atrophy in patients with diseases such as CHF and CKD.

Angiotensin type 1 receptor mediates renal production and conversion of prostaglandins E2 to F2α in conscious diabetic rats.

Previous studies demonstrated that stimulation of angiotensin subtype 1 receptor (AT1R) led to increased renal generation of prostaglandins E2 (PGE2) and renal inflammation. In turn, PGE2 increases AT1R activity. The conversion of PGE2 to the less active metabolite prostaglandin F2α (PGF2α) via 9-ketoreductase interrupts this feedback loop. The effects of diabetes on the interface between AT1R, PGE2 and PGF2α are not well established. We hypothesized that in diabetes, an aberrant AT1R activity enhances the biosynthesis of PGE2 and impairs the activity of PGE 9-ketoreductase, leading to accumulation of PGE2. Using microdialysis technique, we monitored renal interstitial fluid levels of angiotensin II (Ang II), PGE2 and PGF2α in control and AT1R blocker, valsartan, treated diabetic rats (N=8 each). We utilized the PGF2α to PGE2 ratio as indirect measure of PGE 9-ketoreductase activity. Diabetes increased renal interstitial fluid levels of Ang II, PGE2 and PGF2α. PGF2α/PGE2 ratio increased by the third week, but declined by the sixth week of diabetes. Valsartan reduced PGE2 and PGF2α levels and increased Ang II and the conversion of PGE2 to PGF2α. Our results suggest that in diabetes, AT1R increases PGE2 generation and reduces conversion of PGE2 to PGF2α with the progression of diabetes.

Cerebroprotective effects of RAS inhibitors: Beyond their cardio-renal actions.

Work on the brain renin-angiotensin system has been explored by various researchers and has led to elucidation of its basic physiologies and behavior, including its role in reabsorption and uptake of body fluid, blood pressure maintenance with angiotensin II being its prominent effector. Currently, this system has been implicated for its newly established effects, which are far beyond its cardio-renal effects accounting for maintenance of cerebral blood flow and cerebroprotection, seizure, in the etiology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and bipolar disorder. In this review, we have discussed the distribution of angiotensin receptor subtypes in the central nervous system (CNS) together with enzymatic pathways leading to active angiotensin ligands and its interaction with angiotensin receptor 2 (AT2) and Mas receptors. Secondly, the use of angiotensin analogues (angiotensin converting enzyme inhibitors and AT1 and/or AT2 receptor blockers) in the treatment and management of the CNS disorders mentioned above has been discussed.

AT1a Receptor Upregulation in the MnPO Following CIH Leads to Sustained Hypertension

Angiotensin type 1 (AT1) receptors play a central role in many forms of neurogenic hypertension. Two distinct subtypes, At1a and AT1b, exist for AT1 receptors. Activation of the AT1a subtype is characterized by increased sympathetic nerve activity and hypertension. The Median Preoptic Nucleus (MnPO) expresses both subtypes of the angiotensin receptor and our lab has previously demonstrated that AT1a message is increased in MnPO brain punches following CIH. This study sought to determine if changes in expression of the angiotensin receptor subtypes play a role in the sustained hypertension that develops from chronic intermittent hypoxia (CIH). We hypothesized that AT1a receptor expression increased and AT1b receptor expression remained unchanged resulting in the sustained elevation in blood pressure from CIH. Rats were microinjected in MnPO with an adeno‐associated virus loaded with a shRNA construct to prevent AT1a expression (shAT1a) or a scramble construct (shSCR). After recovery, rats were exposed to a 7 day CIH or normoxic protocol. Laser Capture Microdissection and qRTPCR was performed to determine the receptor subtype expression in MnPO with ribosomal subunit S18 as the control. shSCR rats exposed to CIH had significantly more AT1a RNA than their normoxic counterparts (P<.05), but their expression of AT1b remained constant. shAT1a CIH rats did not exhibit the sustained component of hypertension found in shSCR CIH animals and their MnPO AT1a message was reduced compared to control. Overall this indicates that the pathophysiological blood pressure increase during CIH is in part mediated by increases in AT1a receptor subtype expression in the MnPO.

Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.

A Role for the Brain RAS in Alzheimer's and Parkinson's Diseases.

The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II (AngII), angiotensin III, angiotensins (IV), angiotensin (1–7), and angiotensin (3–7). These ligands interact with several receptor proteins including AT1, AT2, AT4, and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as research efforts focused on the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogs capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. AngII and AngIV have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogs in the treatment of animal models of AD and PD. These AngIV analogs act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.