In addition a substantial knowledge has been gained about

In addition, a substantial knowledge has been gained about the main properties of AT1R, such as ligand preference, signaling, regulation, and trafficking. However, it is less known how AT1R and other plasma membrane receptors affect each other’s function, and how these crosstalk mechanisms can be utilized in the clinical practice. The new results in the field of receptor crosstalk can reveal not just new drug targets, but can also explain certain interactions between pharmaceutical compounds. In this review, we highlight the traditional and novel features of AT1 angiotensin receptor (AT1R), which is a prototypical GPCR, and can be considered as paradigm for other GPCRs not only in its pleiotropic functions and action of mechanisms but also in its clinical importance and druggability.
The overactivity of AT1R is detrimental, induces pathophysiological conditions, and frequently associated with various diseases especially in the cardiovascular system and in the kidney. Due to the complexity of the AT1R signaling, the various cell/tissue/organ dysfunctions could be promoted by several parallel mechanisms. The growth factor transactivation (mainly EGFR) is accounted as the key player in AngII-induced maleficent cardiac and vascular hyperplasia and hypertrophy [90]. In addition, excessive AngII-induced reactive oxygen species (ROS) production can lead to oxidative stress within the cells by promoting lipid, protein, and nucleic BMS 753 oxidations. Depending on the type of cells the oxidative stress itself can result in endothelial dysfunction, cardiovascular remodeling, hypertension, cardiac and vascular smooth muscle cell hypertrophy, diabetes, atherosclerosis [91]. AngII also induces inflammatory signals [92], and the proinflammatory actions of AT1R were implicated in the development of several diseases including hypertension, myocardial and renal fibrosis [93], [94]. On top of the cardiovascular and renal symptoms, the deleterious AngII signaling is also implicated in metabolic diseases and diabetes based on the results of clinical studies using various AT1R blockers [95], [96]. The mechanisms which lead to those conditions are not fully understood, although it is well established that insulin resistance can be caused by excessive AngII action and the blockade of RAS improves the insulin sensitivity [97].
Concluding remarks In recent years, the high-resolution crystal structures of antagonist-bound AT1R greatly improved our understanding of the molecular aspects of AT1R functions. However, there is still an urgent need for the structures of both unbiased and biased agonist-bound AT1Rs, which could aid the development of biased compounds with better pharmacodynamic profile. Although TRV120027 failed in a trial of acute heart failure, investigation of biased drugs in other diseases is highly desirable to answer whether these compounds be could be applied in clinical practice. The new insights of receptor cross-talk mechanisms showed that AT1R is much more complex than previously appreciated. Further studies are needed to answer whether the cross-talk mechanisms of AT1R could be successfully targeted in the treatment of diseases.
Conflicts of interest
Acknowledgements This work was supported by the Hungarian National Research, Development and Innovation Fund (NKFI K116954 and NVKP_16-1-2016-0039), and the ÚNKP-17-3-III-SE-23New National Excellence Program of the Ministry of Human Capacities (ADT).
Objectives and limitations of the present review
Revisiting the canonical brain Renin-Angiotensin System. Increasing evidence strongly suggests that the brain Renin-Angiotensin System (RAS) needs critical revision. This review will only reference those publications that, in the view of this author, revealed results obtained with validated methods. Validated methods include film and in situ autoradiography to detect binding sites, and in situ hybridization and qPCR to detect and quantify gene expression. At present, antibodies to study RAS components may not be used unless fully characterized, as explained below.