Elsevier

Cellular Signalling

Volume 26, Issue 10, October 2014, Pages 2147-2160
Cellular Signalling

Review
A century old renin–angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology

https://doi.org/10.1016/j.cellsig.2014.06.011Get rights and content

Highlights

  • ACE–Ang II–AT1 R axis vs. ACE2–Ang (1–7)–Mas R axis in the RAAS cascade

  • Gq and G12/13-mediated signal transduction and growth factor receptor transactivation

  • MAPK signaling by AT1 R-mediated G protein activation and β-arrestin recruitment

  • AT1 receptor-coupled Gβγ signaling and NADPH oxidase activation

  • G protein-dependent and G protein-independent activation of JAK2/STAT signals

Abstract

Ang II, the primary effector pleiotropic hormone of the renin–angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1–7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.

Introduction

The renin–angiotensin system (RAS) functions as an endocrine system to play a key role in cardiovascular and renal physiology. Its overactivation is implicated in the induction and progression of hypertension, atherosclerosis, cardiac hypertrophy, heart failure, ischemic heart disease, and renovascular disorders [1], [2], [3], [4], [5]. Angiotensin II (Ang II), the principal component of the RAS cascade, has diverse physiological actions regulating blood pressure and salt/water balance through a variety of effects that affects the function of most of the organs including heart, kidney, adrenal gland, vasculature and central nervous system. Chronic stimulation or overactivation produces deleterious effects on cardiovascular and renal function [2], [3].

In 1898, Tigerstedt and Bergman at the Karolinska Institute reported the pressor effect of rabbit renal tissue extracts and named the substance renin, because it was extracted from kidneys [6]. In 1934, Harry Goldblatt induced hypertension in dogs by clamping the renal artery [7]. Soon after this event, scientists in the Medical School of the University of Buenos Aires, Argentina, and in the Eli-Lilly Laboratories at Indianapolis, USA, employed the Goldblatt technique and demonstrated renal secretion of a pressor agent similar to that of renin. Both teams described the presence of a novel compound in the renal vein blood of the ischemic kidney that had a short pressor effect. The researchers at the Buenos Aires called the compound ‘hypertensin’, whereas at the Eli-Lilly Lab it was called ‘angiotonin’. In 1958, Page and Braun-Menéndez combined both terms (angiotonin and hypertensin) and agreed to use a name derived from half of each original name, ‘angiotensin’ [8], [9]. Since then several components of RAS have been identified that play physiopathological role in cardiovascular and renal systems. The selected discoveries of RAS components and their target receptors are summarized in Table 1.

Ang II exerts its effects by binding to receptors in target tissues or organs. Two major subtypes of Ang II receptors, AT1 and AT2 were identified by selective ligands and were later characterized as G protein-coupled receptors. Site directed mutagenesis and molecular-dynamics simulation studies have identified the specific amino acids on Ang II and the type of binding interactions with the receptor determinants for ligand binding activation and signal transduction. On the receptor, the extracellular loops and the transmembrane domains are involved in defining the agonistic activity of Ang II. G protein interaction occurs on the transmembrane domain at the amino terminus and the cytoplasmic domains of the 2nd and 3rd intracellular loops [192]. The carboxy terminal tail of the receptor contains numerous serine and threonine residues that are probable sites for phosphorylation by G protein receptor kinases. Phosphorylation negates further G protein stimulation and simultaneously recruits β-arrestins that initiate receptor internalization [10], [11], [12]. The β-arrestin-scaffolded signaling mediates ‘secondary signaling’ involving multiples kinases that link to cytoprotective downstream signaling molecules. The selective G protein-independent signaling has led to the development of ‘biased agonists’ that activate G protein-independent signaling while blocking the detrimental actions on G protein activation, thus, demonstrating their role in cardiovascular diseases. Additionally, Ang II through AT1 receptors stimulates multiple signaling pathways, crosstalk with several tyrosine kinases, and transactivates growth factor receptors. This review focuses on recent advances in understanding the cardiovascular modulatory role of new components of RAS. Furthermore, we discuss in detail the Ang II–AT1 receptor interactions that discern G protein-dependent from G protein-independent signaling pathways, and the mechanisms that influence the cardiovascular physiological and pathological effects of the RAS.

Section snippets

Components of the RAS

Formation of renin from prorenin is an initial and rate-limiting step of the RAS. They are both initiators of the RAS signaling cascade and activators of tissue-dependent and -independent signal transduction. Renin exerts its activity by converting angiotensinogen (AOG) to angiotensin I (Ang I), which is converted into Ang II by angiotensin converting enzyme (ACE) [10]. Notably, Ang (1–12), which is also cleaved from AOG by an unidentified non-renin enzyme, is converted to Ang II largely by

Ang-II-mediated cellular signal transduction

Ang II-induced activation of the AT1 receptor regulates cardiovascular and renal physiology. Besides the physiological role, Ang II exerts an array of diverse pathological actions in heart, blood vessels, kidney, adrenal gland, liver, smooth muscle, skeletal muscle, pancreatic islets and other cell types [11], [68], [69]. The activation of AT1 receptors transduces G protein-dependent and G protein-independent signals. AT1 receptors via G protein activation stimulate phospholipase C (PLC),

Conclusions and perspectives

RAS plays a pivotal role in the physiopathology of the cardiovascular and renal system. Ang II, the main effector molecule of the RAS, binds AT1 receptors mediating physiological effects of blood pressure regulation and salt/water balalnce. However, the abnormal and chronic activation of AT1 receptors by excessive Ang II often causes deleterious effects on cardiovascular and renal system. Besides Ang II, a few more important players of the RAS such as Ang (1–7), alamandine, Ang A,

Conflict of interest

There is no conflict of interest.

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    The opinions expressed herein are those of GJ and do not necessarily reflect those of the US Food and Drug Administration.

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