Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions.
Ontology highlight
ABSTRACT:
SUBMITTER: Catarata MJ
PROVIDER: S-EPMC7352181 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions.
Catarata Maria Joana MJ Ribeiro Ricardo R Oliveira Maria José MJ Robalo Cordeiro Carlos C Medeiros Rui R
Cancers 20200603 6
The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supportin ...[more]
Similar Datasets
Project description:To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune-checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin-angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAF). Last, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8+ T cell-dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD-1/PD-L1 immune-checkpoint blockade therapy.
| S-EPMC5765296 | biostudies-literature
Project description:Pulmonary fibrosis is a serious lung disorder that can lead to respiratory failure. Here we show that transgenic mice expressing active renin from the liver (RenTgMK) developed progressive pulmonary fibrosis leading to impaired pulmonary function. Histological analyses revealed a marked increase in extracellular matrix (ECM) deposition and decrease in alveolar size in the lungs of RenTgMK mice compared to wild-type (WT) littermates, accompanied with increased expression of ECM proteins and fibrogenic factors. The increase in lung fibrosis led to a substantial decrease in respiratory system compliance. Two-week treatment with aliskiren (renin inhibitor) or losartan (AT1 antagonist) ameliorated pulmonary ECM deposition, blocked the induction of ECM proteins and fibrogenic factors and improved respiratory compliance in RenTgMK mice, confirming a critical role of the renin-Ang II-AT1 cascade in promoting pulmonary fibrogenesis. However, when RenTgMK mice were treated with hydralazine (a smooth muscle relaxant), the blood pressure was normalized but the lung fibrotic abnormalities, fibrogenic gene induction and pulmonary elasticity were not corrected. Moreover, intratracheal instillation of lipopolysaccharide induced more severe lung injury in RenTgMK mice compared to WT littermates. These observations demonstrate that the renin-angiotensin system is a key mediator of lung fibrosis, and its pro-fibrotic effect is independent of blood pressure.
| S-EPMC4616037 | biostudies-literature
Project description: Not available
| S-EPMC8019581 | biostudies-literature
Project description:Background:The Dietary Approaches to Stop Hypertension (DASH) diet is widely recommended to lower blood pressure, but its mechanisms of action are unclear. Lines of evidence suggest an interaction with the renin-angiotensin-aldosterone system (RAAS). Objective:We conducted a randomized, controlled, cross-over feeding trial to test RAAS-related mechanisms underlying the DASH diet in patients with isolated systolic hypertension. Methods:Participants entered a 1-wk run-in period on a control (CON) diet and then consumed the DASH or CON diets for 4 wk each in randomized sequence. Calorie content was controlled to maintain weight, and sodium intake was set at 3 g daily. After each diet, participants had hormonal and hemodynamic assessments obtained at baseline, in response to RAAS inhibition with captopril (CAP) 25 mg, and to graded angiotensin II (AngII) infusions (1 ng/kg and 3 ng/kg × 45 min). Primary outcomes were mean arterial pressure (MAP) and renal blood flow (RBF), and secondary outcomes were diastolic function, pulse wave velocity (PWV), plasma renin activity (PRA), and aldosterone (ALDO) responses by diet. Results:In total, 44 (19 female) participants completed the study. DASH + CAP significantly lowered MAP compared with CON + CAP (83 ± 11 mmHg compared with 88 ± 14 mmHg, P <0.01). RBF was increased with DASH + CAP compared with CON + CAP (486 ± 149 cc/min compared with 451 ± 171 cc/min, P <0.001). Study diet did not change PWV but CAP reduced diastolic function on the DASH diet (P <0.05). DASH + CAP significantly increased PRA compared with CON + CAP (1.52 ± 1.78 ng/mL/min compared with 0.89 ± 1.17 ng/mL/min; P <0.001). ALDO sensitivity to AngII infusion was greater with DASH when compared to CON (17.4 ± 7.7 ng/mL compared with 13.8 ± 6.2 ng/dL, P <0.05) as was DASH + CAP compared with CON + CAP (15.1 ± 5.3 ng/dL compared with 13.1 ± 5.9 ng/mL, P <0.05). Conclusions:The DASH diet interacts with the RAAS resulting in vascular and hormonal responses similar to a natriuretic effect, which appears to augment the hypotensive effect of angiotensin-converting enzyme (ACE) inhibition in individuals with isolated systolic hypertension. This trial was registered at clinicaltrials.gov as NCT00123006.
| S-EPMC6735835 | biostudies-literature
Project description:Antenatal maternal hypoxia (AMH) can lead to intrauterine growth restriction (IUGR), as well as idiopathic pulmonary hypertension of newborn and adult, the latter of which may be a consequence of alterations in the local pulmonary renin-angiotensin system (RAS). Little is known of these adaptations, however. Thus, we tested the hypothesis that antenatal maternal hypoxia is associated with alterations in gene and protein expression of the pulmonary renin-angiotensin system, which may play an important role in pulmonary disorders in the offspring. In FVB/NJ mice, we studied messenger RNA (mRNA) and protein expression, as well as promoter DNA methylation and microRNA (miRNA) levels in response to 48 hours hypoxia (10.5% O(2)) at 15.5 day post coitum (DPC). In response to AMH, the pulmonary mRNA levels of angiotensin-converting enzyme (ACE) 1.2, ACE-2, and angiotensin II type 1b (AT-1b) receptors were increased significantly, as compared to controls (N = 4). In response to antenatal hypoxia, pulmonary protein levels of renin and ACE-2 also were increased significantly, whereas ACE-1 protein expression was reduced. In fetal lungs, we also observed reduced expression of the miRNAs: mmu-mir -199b, -27b, -200b, and -468 that putatively increase the translation of renin, ACE-1, ACE-2, and AT-1 receptors, respectively. In response to AMH, promoter methylation of ACE was unchanged. We conclude that AMH leads to changes in expression of pulmonary RAS of fetal mice. The possible implications of these changes for the regulation of pulmonary vascular contractility in later life remain to be explored.
| S-EPMC3826267 | biostudies-literature
Project description:The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.
| S-EPMC7525006 | biostudies-literature
Project description:It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.
| S-EPMC8083494 | biostudies-literature
Project description:OBJECTIVE: To explore the association between epistasis among related genes of the renin-angiotensin system (RAS) and type 2 diabetes. RESEARCH DESIGN AND METHODS: Gene polymorphisms were genotyped in 394 type 2 diabetic patients and 418 healthy control subjects in this case-control study. We used the multifactor dimensionality reduction method to identify gene-gene interactions. RESULTS: No single locus was associated with type 2 diabetes, except for the insert/deletion (I/D) polymorphism of the ACE gene in female subjects. In multi-locus analyses, in male subjects the model of rs2106809 (ACE2), rs220721 (Mas), rs699 (AGT), and I/D (ACE) was significant (P = 0.043). This combination was associated with a 4.00 times (95% CI 2.51-6.38; P < 0.0001) greater prevalence of type 2 diabetes. In female subjects, the model of rs2106809 (ACE2), I/D (ACE), and rs1403543 (AGTR2) was significant (P = 0.012). This three-locus combination was associated with a 2.76 times (1.91-3.97; P < 0.0001) greater prevalence of type 2 diabetes. CONCLUSIONS: Interactions among RAS-related genes were associated with type 2 diabetes in a Chinese population.
| S-EPMC2945173 | biostudies-literature
Project description:The concept of "pharmacogenomics" or "pharmacogenetics" promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the most plausible candidates for the application of this approach in the area of hypertension. For the past two decades, genetic variants of the RAS have been tested for association with blood pressure response, but the results have been inconsistent. The problems have been attributed to many issues, but the most fundamental concern is thought to be the statistical power of the studies. Therefore, we have tried to put together a new systematic review using a database search including only recent reports with adequate numbers of subjects, and 11 reports were identified. From the results, we were able to draw conclusions with nearly consistent findings that the conventional genetic variants of the system (i.e., the ACE I/D, AGT M235T, AT1 A1166C, and AT2 variant) are not associated with antihypertensive effects by RAS blockade, at least by one individual SNP. By contrast, significant associations have been reported (by one report each) for AGT rs7079, AT1 haplotype, REN, and ACE2. For these variants, further evaluations and confirmation are anticipated.
| S-EPMC3179582 | biostudies-literature
Project description:Objective The intrarenal renin-angiotensin system (RAS) is activated in chronic kidney disease (CKD) patients and is not suppressed at night in CKD patients showing nocturnal hypertension, contributing to renal damage. Furthermore, changes in RAS inhibitor administration from morning to evening, namely chronotherapy, ameliorates renal damage at night. We attempted to clarify whether or not chronotherapy ameliorates renal damage by suppressing the intrarenal RAS activity. Methods We recruited 34 CKD patients with RAS inhibitors in the morning. We conducted ambulatory blood pressure (BP) monitoring and urine collection and evaluated urinary albumin (Alb) and angiotensinogen (AGT), which are surrogate markers for intrarenal RAS activity during the day and at night, respectively. The same experiments were conducted after changing the administration time. The ratio of values associated with morning versus evening dosing was defined as the morning to evening (M/E) ratio. Results The M/E ratio of urinary Alb had a significant and positive relationship with that of urinary AGT during the day and at night in all CKD patients. However, no significant relationships were found between the M/E ratios of urinary Alb and AGT using multiple linear regression analyses. Conversely, there was a significant and positive relationship between the M/E ratios of urinary Alb and AGT at night but not during the day in CKD patients whose estimated glomerular filtration rate was <45 mL/min/1.73 m2 and whose night-to-day ratio of systolic BP was >0.90, even after adjustment. Conclusion This study indicated that chronotherapy with RAS inhibitors improved the renal damage via intrarenal RAS suppression, especially in CKD patients with an impaired renal function and nocturnal hypertension.
| S-EPMC7578605 | biostudies-literature