Corrêa et al. Critical Care (2015) 19:98 DOI 10.1186/s13054-015-0802-3 REVIEW Angiotensin II in septic shock Thiago D Corrêa1, Jukka Takala2,3 and Stephan M Jakob2,3* The renin-angiotensin system Abstract Since the discovery of renin by Robert Tigerstedt and This article is one of ten reviews selected from the Per Gunnar Bergman in 1898, a lot of progress has been Annual Update in Intensive Care and Emergency made towards better understanding of the role of the Medicine 2015 and co-published as a series in Critical RAS in body homeostasis and in disease. The classical Care. Other articles in the series can be found online circulating RAS includes angiotensinogen (the precursor at http://ccforum.com/series/annualupdate2015. of angiotensin), the enzymes renin and angiotensin con- Further information about the Annual Update in verting enzyme (ACE), which produces the bioactive Intensive Care and Emergency Medicine is available angiotensin II, and its receptors, AT-1 and AT-2. Aldos- from http://www.springer.com/series/8901. terone is often considered together with the circulating RAS, then referred to as the RAAS (renin-angiotensin- aldosterone system). The major components of the clas- Introduction sical ‘circulating’ RAS were described at the beginning of Systemic vasodilatation and arterial hypotension are the 1970s. In the subsequent decades, knowledge about landmarks of septic shock. Whenever fluid resuscitation angiotensin receptors and the complex interaction be- fails to restore arterial blood pressure and tissue perfu- tween the RAS and other neuroendocrine pathways has sion, vasopressors agents are necessary [1]. Norepineph- increased [5]. One of the most remarkable advances has α rine, a strong -adrenergic agonist, is the standard been the discovery of a tissue (or local) RAS, and more vasopressor to treat septic shock-induced hypotension recently, the discovery of an intracellular RAS [8]. [1]. Adrenergic vasopressors have been associated with The local RAS contains all the components of the cir- several detrimental effects, including organ dysfunction culating RAS and exerts different functions in different and increased mortality [2,3]. Therefore, alternative organs. The local RAS has been identified in heart, agents have been proposed, yet with disappointing re- brain, kidney, pancreas, and lymphatic and adipose tis- sults so far [4]. sues. It can operate independently, as in the brain, or in The renin-angiotensin system (RAS) provides an im- close connection with the circulating RAS, as in the kid- portant physiologic mechanism to prevent systemic neys and the heart [5]. While the circulating RAS is hypotension under hypovolemic conditions, such as mainly responsible for blood pressure control and fluid unresuscitated septic shock [5]. In addition to its clas- and electrolyte homeostasis, the local RAS is predomin- sical hemodynamic function of regulating arterial blood antly related to inflammatory processes, modulating vas- pressure, angiotensin II plays a key role in several bio- cular permeability, apoptosis, cellular growth, migration logical processes, including cell growth, apoptosis, in- and differentiation [6]. flammatory response, and coagulation. It may also affect mitochondrial function [6,7]. This review briefly discusses the main physiological Agiontensin II production functions of the RAS, and presents recent evidence sug- Juxtaglomerular cells of the renal afferent arteriole are gesting a role for exogenous angiotensin II administra- responsible for renin synthesis. Renin, a proteolytic en- tion as a vasopressor in septic shock. zyme, is stored as an inactive form, called pro-renin. Extracellular fluid volume depletion and/or decreased arterial blood pressure trigger several enzymatic reac- * Correspondence: [email protected] tions resulting in the release of active renin into sur- 2 Department of Intensive Care Medicine, Bern University Hospital, Inselspital, rounding tissues and the systemic circulation. However, Bern, Switzerland 3University of Bern, Bern, Switzerland renin has no hemodynamic effects (Figure 1) [8]. Full list of author information is available at the end of the article © 2015 Springer-Verlag and BioMed Central. This article is co-published by agreement with Springer-Verlag. Permission for reuse must be sought from the publisher. Corrêa et al. Critical Care (2015) 19:98 Page 2 of 6 Figure 1 Overview of the renin-angiotensin system. MAP: mean arterial blood pressure; AT: angiotensin; ACE: angiotensin-converting enzyme; AMPA: aminopeptidase A; AMPM: aminopeptidase M; *: ACE is present mainly in lung capillaries, although it can also be found in the plasma and vascular beds of other organs, such as the kidneys, brain, heart and skeletal muscle. Angiotensin I, a decapeptide with weak biological ac- Angiotensin II receptors tivity, is produced from angiotensinogen, an α2-globulin The physiological effects of angiotensin II result from its produced primarily in the liver and, to a lesser extent, in binding to specific G protein-coupled receptors. So far, the kidneys and other organs. Angiotensin is rapidly four angiotensin receptors have been described: AT-1, converted to angiotensin II by an ACE and, to a lesser AT-2, AT-4 and Mas [11]. Additionally, two isoforms of extent, by other chymases stored in secretory granules of AT-1 receptors (AT-1a and AT-1b) have been identified mast cells. Angiotensin II, an octapeptide, has strong in rodents [12,13]. It has been postulated that human vasopressor activity [8]. cells express only AT-1a receptors, located in the kidneys, ACE is present mainly in lung capillaries, although it vascular smooth muscle, heart, brain, adrenals, pituitary can also be found in the plasma and vascular beds of gland, liver and several other organs and tissues [11]. other organs, such as the kidneys, brain, heart and skel- The major physiological activities of angiotensin II are etal muscle. The action of angiotensin II is terminated mediated by AT-1 receptors. Thereby, angiotensin II acts by its rapid degradation into angiotensin 2–8 heptapep- to control arterial blood pressure, aldosterone release by tide (angiotensin III) and ultimately into angiotensin 3–8 the adrenal zona glomerulosa, sodium and water re- heptapeptide (angiotensin IV) by aminopeptidases A and absorption in the proximal tubular cells, and vasopressin M, respectively [8]. ACE-2 is a carboxypeptidase respon- secretion (Figure 1) [14]. When chronically stimulated, sible for the production of angiotensin 1–9 from angio- AT-1 receptors have been shown to mediate cardiac tensin I and angiotensin 1–7 from angiotensin II [9,10]. hypertrophy and induce cardiac remodeling [15]. Angiotensin 1–7 is a heptapeptide, which produces The function of AT-2 receptors in adults has not been vasodilatation mediated by its interaction with the completely determined and some authors suggest that prostaglandin-bradykinin-nitric oxide system [10]. their stimulation might counteract the AT-1 effects on The balance between ACE and ACE-2 may play an im- blood pressure regulation, inflammation and cell growth portant role in cardiovascular pathophysiology by modu- [11]. Indeed, angiotensin II binding to AT-2 receptors lating and controlling angiotensin II blood concentrations. results in vasodilatation and decreased systemic vascular The RAS is primary regulated by a negative feedback ef- resistance (Figure 1) [5]. fect of angiotensin II on renin production by the juxtaglo- A large number of experimental studies have shown merular cells of the renal afferent arteriole [5]. that angiotensin II mediates countless key elements of Corrêa et al. Critical Care (2015) 19:98 Page 3 of 6 inflammatory processes [6] (Figure 2). By binding to AT-1 volume and arterial blood pressure restoration in septic receptors, angiotensin II enhances the expression of pro- shock [32]. These mechanisms are sympathetic nervous inflammatory mediators, increases vascular permeability system activation, the release of arginine vasopressin by by inducing vascular endothelial growth factor (VEGF), the posterior pituitary gland, inhibition of atrial and cere- and stimulates the expression of endothelial adhesion bral natriuretic peptide secretion from the atria of the molecules (P-selectin and E-selectin), intercellular adhe- heart, and the increase in renin secretion by the juxtaglo- sion molecule-1 (ICAM-1) and vascular cell adhesion merular cells, resulting in elevated angiotensin II plasma molecule-1 (VCAM-1) (Figure 2) [6]. Angiotensin II also levels and an increased secretion of aldosterone from the promotes reactive oxygen species (ROS) production, cell adrenal cortex [32]. growth, apoptosis, angiogenesis, endothelial dysfunction, During sepsis, the activity of plasma renin, angiotensin cell migration and differentiation, leukocyte rolling, adhe- I and angiotensin II are increased [19]. Despite the high sion and migration, extracellular matrix remodeling. Fi- angiotensin II plasma levels, pronounced hypotension, nally, it can play a role in multiple intracellular signaling associated with a reduced vasopressor effect of angioten- pathways leading to organ and mitochondrial injury [16]. sin II, has been reported [17]. Moreover, RAS activation contributes to oxidative stress and endothelial dysfunc- The renin-angiotensin system in sepsis tion [24], which has been associated with development Activation of the RAS during sepsis is a well know of kidney [33] and pulmonary [25,26] injury and with phenomenon, observed in experimental [17] and