Purpose of the Review The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective. Recent Findings The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. Summary Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels. Keywords Renin. Prorenin receptor. Angiotensin receptor. Biased agonist. Blood pressure. Neurophysiology This article is part of the Topical Collection on Inflammation and Cardiovascular Diseases
Endoplasmic reticulum (ER) stress is implicated in many chronic diseases, but very little is known about how the unfolded protein response (UPR) responds to persistent ER stress in vivo. Here, we experimentally reconstituted chronic ER stress in the mouse liver, using repeated injection of a low dose of the ER stressor tunicamycin. Paradoxically, this treatment led to feedback-mediated suppression of a select group of mRNAs, including those encoding the ER chaperones BiP and GRP94. This suppression was due to both silencing of the ATF6α pathway of UPR-dependent transcription and enhancement of mRNA degradation, possibly via regulated IRE1-dependent decay (RIDD). The suppression of mRNA encoding BiP was phenocopied by ectopic overexpression of BiP protein, and was also observed in obese mice. Our findings suggest that persistent cycles of UPR activation and deactivation create an altered, quasi-stable setpoint for UPR-dependent transcriptional regulation—an outcome that could be relevant to conditions such as metabolic syndrome.DOI: http://dx.doi.org/10.7554/eLife.20390.001
Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival in patients with advanced HGSC. Spatial transcriptomics and single-cell RNA sequencing data were integrated to distinguish tumor and stroma regions, and a computational method was developed to investigate spatially resolved ligand-receptor interactions between various tumor and CAF subtypes in the TME. A specific subtype of CAFs and its spatial location relative to a particular ovarian cancer cell subtype in the TME correlated with long-term survival in advanced HGSC patients. Also, increased APOE-LRP5 crosstalk occurred at the stroma-tumor interface in tumor tissues from STS compared to LTS. These findings were validated using multiplex immunohistochemistry. Overall, this spatial transcriptomics analysis revealed spatially resolved CAF-tumor crosstalk signaling networks in the ovarian TME that are associated with long-term survival of HGSC patients. Further studies to confirm whether such crosstalk plays a role in modulating the malignant phenotype of HGSC and could serve as a predictive biomarker of patient survival are warranted.
The brain specific isoform of renin (Ren-b), has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to DOCA-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after DOCA-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not due to changes in food intake, energy absorption or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue (BAT), suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased BAT glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.
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