- Review
- Open access
- Published:
Impaired angiotensin II signaling in septic shock
Annals of Intensive Care volume 14, Article number: 89 (2024)
Abstract
Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II—angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin–angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin–angiotensin–aldosterone system alterations in septic shock should help to decipher patients’ phenotypes and to implement targeted interventions.
Background
Septic shock represents the most severe form of sepsis. Septic shock is characterized by “profound circulatory, cellular, and metabolic abnormalities” and associated with high mortality [1]. Vasodilation is the primary feature of sepsis-associated circulatory failure, although a component of hypovolemia and/or myocardial depression is often present [2]. Accordingly, vasopressor support is the cornerstone of the symptomatic management of septic shock and relies on the use of norepinephrine on the frontline and vasopressin as a second line agent [3]. More recently, the use of angiotensin II has been suggested for catecholamine-refractory vasodilatory shock, mostly of septic origin [4]. The renin–angiotensin–aldosterone system (RAAS) is a complex homeostatic system with implication in numerous biological processes, with blood pressure maintenance and sodium homeostasis at the forefront. While overactivation of this system has been well-documented in chronic cardiovascular and kidney diseases, leading to a detrimental cycle of excessive vasoconstriction, sodium retention, and maladaptive repair, it is essential to remind that the RAAS primarily acts as a compensatory mechanism to cope with acute aggression. Accordingly, its integrity is crucial to maintain hemodynamics during circulatory stress. Recent data nevertheless suggest that this homeostatic mechanism is altered during the course of septic shock with potential therapeutic implications.
Starting with a comprehensive overview of the RAAS and its role in maintaining homeostasis, this concise translational review aims to summarize the available evidence regarding RAAS alterations during septic shock, and to discuss the consequences and potential therapeutic strategies.
Overview of the RAAS
The renin–angiotensin–aldosterone system is a complex network of over thirty peptides, enzymes, receptors, and associated proteins (Fig. 1). The formation of all RAAS effector peptides occurs through the sequential proteolytic cleavage of angiotensinogen, also known as the RAAS proteolytic cascade. Angiotensinogen is an α2-glycoprotein produced by hepatocytes and cleaved by renin to generate the inactive decapeptide angiotensin I. Renin is an enzyme produced by the juxtaglomerular cells of the kidney with two modes of release: a constitutive release of an inactive or pro-renin form; and a regulated pulsatile release of active renin, influenced by various stimuli, most notably a drop in renal perfusion pressure, a low salt intake or sympathetic nervous system activation (Fig. 2) [5]. This finely tuned regulation of renin release operates within minutes to ensure a precise and timely adjustment of RAAS input and its downstream effects. A slower induction of angiotensinogen synthesis and release occurs in response to multiple stress factors such as glucocorticoids, cytokines (interleukin-1 and -6, interferon-γ, tumor necrosis factor α), estrogens, triiodothyronine and angiotensin II (via a positive feedback loop), aiming at maintaining a sufficient substrate supply during prolonged stress conditions [6]. However, it should be noted that the synthesis of angiotensinogen depends on the integrity of hepatic function [7]. Since the circulating angiotensinogen concentration is close to the Michaelis–Menten constant of renin, even discrete changes in its concentration are susceptible to affect angiotensin I generation [8].
The inactive peptide angiotensin I is subsequently cleaved into the principal RAAS effector: the octapeptide angiotensin II by the action of the angiotensin-converting enzyme (ACE). This enzyme exists in two forms: a membrane-bound form, mainly expressed by pulmonary endothelial cells, and a soluble or circulating form. Importantly, data from the literature suggest that, at least in physiological circumstances, most of the conversion activity is carried out by membrane-bound ACE, quantitatively more important [9]. Angiotensin II exerts its main effect via the angiotensin II, type 1 receptor (AT1R), mediating vasoconstriction, cell proliferation, pro-fibrotic and pro-inflammatory signals, as well as stimulating aldosterone release from the adrenal gland [10]. Additionally, AT1R stimulation on juxta-glomerular cells inhibits renin release, in a negative biofeedback mechanism [5, 10]. Another receptor, termed the angiotensin II type 2 receptor (AT2R) elicits opposite effects [10]. Angiotensin II is further cleaved into angiotensin III by aminopeptidase A and subsequently into angiotensin IV by aminopeptidase N [10]. Alternatively, angiotensin II can be directly cleaved into angiotensin IV by dipeptidyl peptidase 3 (DPP3) [11]. Angiotensin III binds to AT1R and AT2R with similar affinity as angiotensin II, thereby producing similar effects, albeit with faster clearance [12]. Angiotensin IV also exhibits low-affinity binding to angiotensin II receptors but also possess a specific receptor initially referred to as the angiotensin IV receptor (AT4R) and later identified as the insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase [10]. Binding of angiotensin IV competitively inhibits IRAP, thereby extending the half-life of its other substrates such as oxytocin or vasopressin [13, 14].
Alongside this well-established “classical” RAAS, a newly recognized “alternative” system has recently been brought to light. Entry into this alternative system can occur at various level. An ACE homolog called angiotensin converting enzyme 2 (ACE2) allows the formation of angiotensin-(1–9) from angiotensin I or angiotensin-(1–7) from angiotensin II [15]. Additionally, angiotensin-(1–7) can be generated by prolyl peptidases from angiotensin II or directly from angiotensin I by neprilysin (NEP) also known as neutral endopeptidase or by thimet oligopeptidase [15]. However, the respective contributions of these enzymes to angiotensin-(1–7) generation remain poorly understood. ACE catalyzes the formation of angiotensin-(1–7) from angiotensin-(1–9) and further converts it into angiotensin-(1–5). Themain effector of this “alternative” system, angiotensin-(1–7) mediates vasodilatory, natriuretic, anti-fibrotic and anti-inflammatory effects through activation of the MAS receptor [15].
Finally, more recent investigations have unveiled the existence of a third group of RAAS peptides known as alatensins. These peptides differ from the previously described ones by the presence of an alanine in the N-terminal position, rather than an arginine. Thus far, two members of the alatensin family have been identified in vivo: angiotensin A or ala1-angiotensin II, and alamandine or ala1-angiotensin-(1–7). Angiotensin A acts as a ligand for both AT1R and AT2R while alamandin exerts its effects through the MAS-related G-protein-coupled receptor D (MRGD) [16, 17]. It is conceivable that future research may uncover additional members of the alatensin family in the years to come [18].
Overall, the classical RAAS could is generally associated with vasoconstrictive, pro-fibrotic, and pro-inflammatory effects, while the alternative RAAS act as a counter-balancing system, mediating vasodilatory, anti-fibrotic, and anti-inflammatory effects. The alatensins represents an intermediate system with angiotensin A resembling angiotensin II and alamandine resembling angiotensin-(1–7). However, due to the rapid conversion of angiotensin A into alamandine, the overall impact effect of the alatensin system tends to resembles that of the alternative RAAS [16, 17]. It is important to note that this dichotomy mainly arises from observations and experiments conducted in chronic settings that may not accurately reflect acute conditions such as circulatory failure. Furthermore, the same peptide can yield different effects depending on the receptor it interacts with (e.g., angiotensin II via AT1R or AT2R) suggesting that the modulation of respective receptor abundance in acute situations may act as a potential modifier of the net peptide action.
Current understanding of the RAAS during septic shock
The RAAS as a compensatory mechanism during circulatory stress
There is a distinct contrast between physiology and pathology regarding RAAS dependency. In purely physiological settings, when salt intake is sufficient and the blood pressure maintenance systems are intact, RAAS integrity appears to be non-essential. For instance, under such conditions, the administration of a renin antagonist or an AT1R antagonist leads to minimal short-term hemodynamic effects in awake healthy animals and humans [19, 20]. It is worth noting that in the same conditions, an ACE inhibitor results in a significant reduction in blood pressure because ACE also catalyzes the degradation of bradykinin, a potent vasodilator [20]. Conversely, the RAAS assumes a pivotal role in stress conditions by facilitating the maintenance of blood pressure primarily through the vasoconstrictive and anti-natriuretic actions of angiotensin II, as well as angiotensin II-induced release of aldosterone, potentiating sodium reabsorption. Therefore, prior sodium depletion unmasks the hypotensive effect of AT1R antagonist in healthy humans [21]. Patients taking RAAS inhibitors are more likely to experience general anesthesia-induced hypotension [22]. In this specific context, it has been elegantly demonstrated that the major systems of blood pressure regulation, namely, the sympathetic system, the vasopressinergic system and the RAAS, are intricately interconnected and capable of compensating for the dysfunction of one another. However when all three systems are compromised, life-threatening hypotension occur [23]. The close interconnection between these three systems is further emphasized by the evidence of synergy among them. For instance, the vasoconstrictive response to angiotensin II is enhanced in presence of norepinephrine or vasopressin [24, 25].
The short-term effect of RAAS on glomerular function relies both on the modulation of renal perfusion pressure, but also on a differential action on the two vascular poles of the glomerulus. Angiotensin II predominantly induces vasoconstriction of the efferent glomerular arteriole rather than of the afferent arteriole [26]. Consequently, the loss of AT1R-dependent vasomotor tone tends to lower glomerular capillary pressure, resulting in a decrease of glomerular filtration rate [26]. In healthy animals and humans, these hemodynamic alterations typically do not translate into significant functional changes. Thus, the administration of an AT1R antagonist to healthy mice or humans does not affect glomerular filtration rate. [27, 28]. However, in a situation of circulatory stress, the use of RAAS inhibitor precipitates the reduction of glomerular filtration rate [26].
Animal models of septic shock have provided compelling evidence regarding the crucial role of RAAS integrity in maintaining systemic and renal hemodynamic. Thus, administration of RAAS inhibitors has been associated with worse systemic hemodynamic and increased severity of acute kidney injury (AKI) in experimental septic shock [29, 30]. It is noteworthy that in the early stage of experimental and human sepsis-associated AKI, the decline in glomerular filtration rate is associated with elevated renal blood flow and reduced renovascular resistances [31]. This decoupling between flow and glomerular filtration may be explained by a preferential efferent arteriole vasodilation, resulting in the loss of post-glomerular resistance leading to decreased glomerular capillary pressure and ultimately a reduction in glomerular filtration rate (Fig. 3). While numerous factors have been implicated in the genesis of vasodilation during sepsis, the preferential involvement of the efferent arteriole suggest that angiotensin II–AT1R signaling inadequately opposes these vasodilating substances. In experimental models of septic shock, angiotensin II restores renal blood flow to control levels and is associated with improved glomerular function [30, 32]. Another hypothesis that may explain the hemodynamic profile of sepsis-associated AKI is the opening of periglomerular shunts. Although the existence of such shunts has been demonstrated in healthy animals, their role in human sepsis-associated AKI remains to be established [33]. Nevertheless, in the presence of a shunt, a decreased in efferent resistance is likely to favor the shunt, with the blood flow following the path of least resistance (Fig. 3). The observation of minimal histologic changes in early sepsis-associated AKI suggests that the aforementioned hemodynamic alterations play a significant role in renal function impairment [30, 34].
RAAS alterations during septic shock
Current evidence suggests that this crucial homeostatic system may falter in the context of septic shock. In critically ill patients, elevated renin concentration has been associated with lower blood pressure, a higher incidence of major adverse kidney events, and increased mortality rate and [35,36,37,38]. During catecholamine-resistant vasodilatory shock, mostly of septic origin, high renin concentration correlates with high circulating angiotensin I concentrations [36]. However, this contrasts with normal or low circulating angiotensin II concentrations [36, 39], resulting in a high angiotensin I/angiotensin II ratio which has been associated with increased mortality [39]. Importantly, these data come from a study that measured circulating angiotensin concentrations using serum to which peptidase inhibitors were added after a first freeze–thaw cycle, which could have permitted ongoing angiotensin processing during initial blood clotting step and thus represents an imperfect methodology. Despite a comparison with healthy controls whose samples were handled similarly, these observations must therefore be interpreted with caution and require confirmation.
All factors considered, the angiotensin I/angiotensin II ratio exhibits an inverse correlation with ACE activity [40]. Consequently, the constatation of a high ratio in critically ill patients has led to the attribution of the observed alterations primarily to an ACE deficiency [36, 39]. Indeed, decreased ACE activity has been found in the subgroup of septic shock patients with acute lung injury, consistent with the dominant pulmonary expression of ACE and suggesting a predominant role of sepsis-associated (pulmonary) endotheliopathy [41,42,43]. Additionally, impaired ACE activity could be linked to the presence of circulating endogenous ACE inhibitors formed during shock [44, 45]. Importantly, a defect of ACE activity also leads to bradykinin accumulation, further worsening vasoplegia [40].
However, several mechanisms may be intertwined in RAAS alterations during septic shock (Fig. 4) (Table 1). In addition to a decreased generation of angiotensin II, enhanced degradation of angiotensin II by peptidases; and/or the unavailability of AT1R could also contribute to defective signaling. Early experiments already demonstrated the progressive rise of plasma angiotensinase activity during endotoxemic shock, in dogs [46]. To date, most of the evidence pertains to increased concentration and activity of circulating DPP3 [47, 48]. This enzyme hydrolyses angiotensin II but not angiotensin I, resulting in an elevated angiotensin I/angiotensin II ratio [49, 50]. Interestingly, both the baseline concentration and kinetics of circulating DPP3 are associated with outcome during sepsis and septic shock [51, 52]. Other enzymes capable of degrading angiotensin II include ACE2. Notably, ACE2 exhibits a higher affinity for angiotensin II than angiotensin I, thus suggesting that an increase in ACE2 activity could theoretically lead to an elevated angiotensin I/angiotensin II ratio [53]. Neverthelessthe role of ACE2 in increased angiotensin II degradation during septic shock remain to be determined. Other angiotensin II-degrading enzymes may also be implicated such as prolyl oligopeptidase or prolyl carboxypeptidase [54]. Additionally, it is worth noting that NEP cleaves angiotensin II into angiotensin-(1–4) and angiotensin-(5–8) and could theoretically by-pass ACE by directly generating angiotensin-(1–7) from angiotensin I. Although the circulating concentration of NEP is increased in critically ill patients [55], such increase is not associated with prognosis, potentially because concentration and activity are dissociated during septic shock, likely due to endogenous inhibitors [56, 57].
Finally, a reduced sensitivity to angiotensin II in septic shock models and patients compared to their healthy counterparts suggests a downstream defect. This impaired signaling could arise from AT1R unavailability, which may result from AT1R internalization or reduced synthesis. The membrane localization of AT1R is known to be modulated by two associated proteins: the AT1R associated protein (ATRAP), which enhances AT1R internalization, and the AT1R associated protein 1 (ARAP1), promoting the recycling of AT1R to the membrane [58, 59]. Interestingly, a single nucleotide polymorphism of ATRAP has been associated with increased ATRAP protein expression in vitro and with increased vasoplegia in patients, as demonstrated by decreased mean arterial pressure during sepsis and post-cardiac surgery [60]. These findings are further linked to increased mortality of patients presenting such polymorphism during septic shock [60]. Conversely, expression of ARAP1 is downregulated during experimental endotoxemia or after in vitro exposition to pro-inflammatory cytokines [61]. Furthermore, experimental endotoxemia in Arap1 knockout mice suggests that the downregulation of ARAP1 expression during sepsis contributes to the development of hypotension by reducing vascular sensitivity to angiotensin II [61]. Additionally, nitric oxide and pro-inflammatory cytokines may cooperate to decrease AT1R gene transcription [62, 63]. Micro-RNA-155, which is overexpressed in both animal and human sepsis, negatively regulates AT1R transcription, ultimately leading to decreased vasoconstrictive responses to angiotensin II [64].
Importantly, the growing utilization of RAAS inhibitors exposes patients to iatrogenic causes of defective AT1R signaling. For instance, the use of renin inhibitor or ACE inhibitors is likely to contribute to an insufficient generation of angiotensin II. Conversely, the use of an angiotensin receptor blocker reduces sensitivity to angiotensin II [65]. It is worth noting that some of these medications have a prolonged half-life and are eliminated through the renal route, exposing patients to long-lasting alterations.
The aforementioned alterations can occur either in isolation or in combination, leading to an uncoupling between RAAS input (renin release) and output (AT1R stimulation). Intriguingly, evidence of such uncoupling could be found in situations of hyperreninemic hypoaldosteronism described several years ago in a subset of critically ill patients while the underlying mechanism remain elusive. These patients, despite consistently elevated plasma renin activity, exhibited abnormally normal or even low plasma aldosterone concentration. Notably, this biochemical profile was more frequently observed in septic shock patients and was associated with higher incidence of AKI as well as lower survival rates [66,67,68].
RAAS-targeted therapy
The only RAAS targeted therapy that has advanced to clinical stages in shock is angiotensin II. In animal models of septic shock, vasopressor support with angiotensin II has been associated with similar systemic hemodynamics compared to norepinephrine [29, 69]. The use of angiotensin II in humans was initially limited to bovine angiotensin II in cases of refractory shock [70, 71]. The development of synthetic human angiotensin II allowed larger-scale evaluation.
The randomized controlled trial ATHOS-3 investigated the efficacy of angiotensin II on top of standard of care in 344 patients with catecholamine-refractory vasodilatory shock, predominantly of septic origin [4]. The primary end point, response with respect to mean arterial pressure at hour 3 after the start of infusion (a response was defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors), was reached more often in patients randomized to angiotensin II, compared to those receiving placebo (69.9% vs 23.4%, p < 0.001). However, there were no significant difference in secondary outcomes such as the mean change in SOFA score at hour 48, or mortality at day 7 or 28. Post-hoc analyses suggested that in patients with AKI requiring renal replacement therapy at study drug initiation, the rate of renal replacement therapy liberation and 28-day survival were greater in the angiotensin II group compared to the placebo group [72]. Despite these interesting and biologically plausible findings, the post-hoc nature of the analysis and the absence of predefined criteria for initiating and discontinuing renal replacement therapy prevent definitive conclusions. Additionally, in patients with baseline renin concentration above the median of ATHOS-3 population, angiotensin II was associated with a significant reduction in 28-day mortality, compared to placebo (50.9% vs 69.9%, p = 0.012), suggesting the potential use of renin as an enrichment biomarker in future trials. At last, in the subgroup of ATHOS-3 patients with acute respiratory distress syndrome, randomization to the angiotensin II arm was associated with improved oxygenation [73]. Despite these encouraging findings, it remains to be prospectively demonstrated that angiotensin II is associated with improved patients-centered outcomes such as survival. Additionally, several questions remain to be answered.
First, it is unclear whether angiotensin II should be administered in all patients with vasodilatory shock. Noticeably, the vasopressor response to angiotensin II is not constant. In ATHOS-3, 30% of patients randomized to angiotensin II did not have a blood pressure response at hour-3 despite the use of large doses (up to 200 ng/kg/min) [4]. Conversely, a hyper-response phenomenon has also been described [74,75,76]. This diversity of response profile could mirror the diversity of RAAS alterations mechanisms described earlier. According to this hypothesis, patients with an isolated angiotensin II generation defect would be likely to be hyper-responsive to exogenous angiotensin II. Conversely, high doses might not be sufficient in patients with increased degradation of angiotensin II and/or AT1R unavailability. In these latter patients, alternative or complementary strategies might be necessary. Second, in ATHOS-3, 80.7% of patients had septic shock. Whether angiotensin II is of benefit in non-septic vasodilatory shock remain to be investigated. The molecular mechanisms underlying RAAS alterations have been primarily described in septic contexts. However, similar alterations might be encountered in non-septic vasodilatory shock. Indeed, elevated renin is associated with prolonged need of vasopressors and the occurrence of acute kidney injury after cardiopulmonary bypass surgery [77]. Nevertheless, the benefit-risk balance of exogenous angiotensin II administration in non-septic situations may differ. Patients with recent cardiac injuries, may raise concerns, and dedicated studies are needed to assess the appropriateness of angiotensin II support in these cases. Third, in ATHOS-3, more than two thirds of subjects were receiving two or more vasopressors prior to study drug administration. Additional research is required to determine whether angiotensin II should be administered as the primary vasopressor or as a secondary or tertiary option. Evaluating the potential benefits of a primary balanced strategy combining norepinephrine, vasopressin, and angiotensin II should also be considered [78].
Finally, the adverse event profile needs further examination. While the rates of adverse events of special interest were similar between the angiotensin II and placebo groups in ATHOS-3, there was a higher incidence of combined arterial and venous thromboembolic events in patients receiving angiotensin II [4, 79]. This observation aligns with the known pro-thrombotic properties of angiotensin II and has led to recommendations for thromboembolism prophylaxis in patients treated with angiotensin II [80].
Future directions and recommendations for RAAS research in experimental models and critically ill patients
We have attempted to synthesize the available translational evidence regarding RAAS alterations during septic shock, their consequences, and potential therapeutic strategies. Nevertheless, further investigation is warranted to gain a comprehensive understanding of RAAS alterations during septic shock. Notably, investigation of alternative RAAS components such as ACE2 and angiotensin-(1–7) appear critical for unraveling the complex contribution of RAAS alterations to circulatory failure. Additionally, exploring the temporal aspects of RAAS alterations throughout the course of disease is essential to inform the selection of optimal therapeutic approaches at different stages of septic shock. Furthermore, a pressing need exists to identify distinct patient phenotypes based on RAAS alterations and translate this understanding into personalized interventions. To achieve a comprehensive understanding of the RAAS in septic shock, rigorous research methodologies and adequate experimental models are indispensable. In this regard, several important points should be highlighted.
Renin measurement alone is insufficient to draw conclusion about the pathophysiological role of the RAAS in pathological situation. Indeed, high renin can result from appropriate feedback to an impaired AT1R signaling or from inappropriate activation of the RAAS leading to more inflammation, oxidative stress and intra-renal vasoconstriction [81]. When the aim is to investigate the mechanistic role of the RAAS in a pathological condition, it appears preferable to couple renin and RAAS peptides measurements and to assess their downstream clinical (e.g., systemic and renal hemodynamic) and biological (e.g., aldosterone secretion) effects. Importantly, when considering the specific role of renin, it is advisable to prioritize an assay measuring active renin concentration or a standardized activity assay with the addition of exogenous angiotensinogen, over the historical “plasma renin activity”. Indeed, plasma renin activity reflects the overall RAAS input and rely not only on renin concentration but also on angiotensinogen concentration in the sample [82]. To prevent falsely elevated results caused by the cryoactivation of pro-renin that occurs within a temperature range of 2 to 8 °C, samples should be frozen and thawed as quickly as possible, and the assay performed at room temperature [83].
Measuring RAAS peptides is challenging and necessitates validated and reproducible methodology. Such measurements face multiple obstacles including short half-life, low concentrations, and high sequence similarity of RAAS peptides as well as ex-vivo generation from circulating angiotensinogen and renin. These pitfalls might be adequately addressed by the use of plasma samples stabilized by peptidases inhibitors upon blood collection and by the use of modern measurements methods such as liquid chromatography coupled with immunoassays or mass spectrometry or [82, 84]. Due to the prolonged clotting time required, the use of serum samples should be avoided. A precise description of the methodology used should always be reported.
To gain a better understanding of the precise mechanism underlying a potential benefit of RAAS modulation, it is desirable to study not only the initial RAAS picture during shock, but also how a specific intervention modifies the system. For instance, the benefits associated with angiotensin II administration may extend beyond the directly observable AT1R-mediated hemodynamic effects, involving additional mechanisms. Negative feedback on renin release could reduce pro-inflammatory effects mediated by renin via the (pro)renin receptor [85,86,87]. Other AT1R-mediated immune effects could participate in pathogen clearance during sepsis [88]. Additionally, exogenous angiotensin II could exert beneficial effects directly through the AT2R receptor or after in vivo conversion into alternative RAAS peptides or alatensins [89].
The translation of observations obtained in animal studies to humans must be done cautiously, given numerous inter-species variations [90]. Therefore, whenever possible, these observations should be validated in several species and, at best, in humans.
From a clinical perspective, the short-term benefit of RAAS modulation should not overshadow the potential long-term side effects associated with the well-established AT1R-mediated pro-inflammatory and pro-fibrotic effects. Therefore, especially when planning human trials, long-term follow-up with vigilant monitoring for adverse cardiovascular and/or renal events is advisable.
Conclusion
While the RAAS is crucial to cope with circulatory stress, alterations of this homeostatic system have been recently demonstrated during septic shock, ultimately leading to impaired angiotensin II signaling. These observations open a new field of research and hopefully new therapeutic avenues susceptible to improve patients’ prognosis. In the next future, a better understanding of RAAS alterations should help to decipher patients’ phenotypes and translate into targeted interventions.
Availability of data and materials
Not applicable.
Abbreviations
- RAAS:
-
Renin–Angiotensin–Aldosterone System
- ACE:
-
Angiotensin-Converting Enzyme
- AT1R:
-
Angiotensin II, Type 1 Receptor
- AT2R:
-
Angiotensin II, Type 2 Receptor
- DPP3:
-
DiPeptidyl Peptidase 3
- AT4R:
-
Angiotensin IV receptor
- IRAP:
-
Insulin-Regulated AminoPeptidase
- ACE2:
-
Angiotensin-Converting Enzyme
- NEP:
-
Neprilysin/neutral endopeptidase
- MRGD:
-
MAS-related G-protein-coupled D receptor
- AKI:
-
Acute kidney injury
- ATRAP:
-
AT1R-Associated Protein
- ARAP1:
-
AT1R-Associated Protein 1
References
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.
Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726–34.
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–247.
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–30.
Schweda F, Kurtz A. Regulation of renin release by local and systemic factors. Rev Physiol Biochem Pharmacol. 2011;161:1–44.
Brasier AR, Li J. Mechanisms for inducible control of angiotensinogen gene transcription. Hypertens Dallas Tex 1979. 1996;27(3):465–75.
Arnal JF, Cudek P, Plouin PF, Guyenne TT, Michel JB, Corvol P. Low angiotensinogen levels are related to the severity and liver dysfunction of congestive heart failure: implications for renin measurements. Am J Med. 1991;90(1):17–22.
Cumin F, Le-Nguyen D, Castro B, Menard J, Corvol P. Comparative enzymatic studies of human renin acting on pure natural or synthetic substrates. Biochim Biophys Acta. 1987;913(1):10–9.
Ng KK, Vane JR. Conversion of angiotensin I to angiotensin II. Nature. 1967;216(5117):762–6.
Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, et al. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev. 2018;98(3):1627–738.
Lee CM, Snyder SH. Dipeptidyl-aminopeptidase III of rat brain. Selective affinity for enkephalin and angiotensin. J Biol Chem. 1982;257(20):12043–50.
Gammelgaard I, Wamberg S, Bie P. Systemic effects of angiotensin III in conscious dogs during acute double blockade of the renin-angiotensin-aldosterone-system. Acta Physiol Oxf Engl. 2006;188(2):129–38.
Albiston AL, McDowall SG, Matsacos D, Sim P, Clune E, Mustafa T, et al. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J Biol Chem. 2001;276(52):48623–6.
Le MT, Vanderheyden PML, Szaszák M, Hunyady L, Vauquelin G. Angiotensin IV is a potent agonist for constitutive active human AT1 receptors. Distinct roles of the N-and C-terminal residues of angiotensin II during AT1 receptor activation. J Biol Chem. 2002;277(26):23107–10.
Santos RA. Angiotensin-(1–7). Hypertens Dallas Tex 1979. 2014;63(6):1138–47.
Jankowski V, Vanholder R, van der Giet M, Tölle M, Karadogan S, Gobom J, et al. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007;27(2):297–302.
Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11.
Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader M. The renin-angiotensin system: going beyond the classical paradigms. Am J Physiol Heart Circ Physiol. 2019;316(5):H958–70.
Christen Y, Waeber B, Nussberger J, Porchet M, Borland RM, Lee RJ, et al. Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II. Circulation. 1991;83(4):1333–42.
Kiowski W, Linder L, Kleinbloesem C, van Brummelen P, Bühler FR. Blood pressure control by the renin-angiotensin system in normotensive subjects. Assessment by angiotensin converting enzyme and renin inhibition. Circulation. 1992;85(1):1–8.
Posternak L, Brunner HR, Gavras H, Brunner DB. Angiotensin II blockade in normal man: interaction of renin and sodium in maintaining blood pressure. Kidney Int. 1977;11(3):197–203.
Roshanov PS, Rochwerg B, Patel A, Salehian O, Duceppe E, Belley-Côté EP, et al. Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN Prospective Cohort. Anesthesiology. 2017;126(1):16–27.
Carp H, Vadhera R, Jayaram A, Garvey D. Endogenous vasopressin and renin-angiotensin systems support blood pressure after epidural block in humans. Anesthesiology. 1994;80(5):1000–7.
Seidelin PH, Coutie WJ, Pai MS, Morton JJ, Struthers AD. The interaction between noradrenaline and angiotensin II in man: evidence for a postsynaptic and against a presynaptic interaction. J Hypertens Suppl Off J Int Soc Hypertens. 1987;5(5):S121-124.
Hidaka T, Tsuneyoshi I, Boyle WA, Onomoto M, Yonetani S, Hamasaki J, et al. Marked synergism between vasopressin and angiotensin II in a human isolated artery. Crit Care Med. 2005;33(11):2613–20.
Hall JE, Coleman TG, Guyton AC, Kastner PR, Granger JP. Control of glomerular filtration rate by circulating angiotensin II. Am J Physiol. 1981;241(3):R190-197.
Burnier M, Waeber B, Brunner HR. Clinical pharmacology of the angiotensin II receptor antagonist losartan potassium in healthy subjects. J Hypertens Suppl Off J Int Soc Hypertens. 1995;13(1):S23-28.
Schnermann J, Huang YG, Briggs JP. Angiotensin II blockade causes acute renal failure in eNOS-deficient mice. J Renin-Angioten-Aldostere Syst JRAAS. 2001;2(1):199–203.
Corrêa TD, Jeger V, Pereira AJ, Takala J, Djafarzadeh S, Jakob SM. Angiotensin II in septic shock: effects on tissue perfusion, organ function, and mitochondrial respiration in a porcine model of fecal peritonitis. Crit Care Med. 2014;42(8):e550-559.
Leisman DE, Fernandes TD, Bijol V, Abraham MN, Lehman JR, Taylor MD, et al. Impaired angiotensin II type 1 receptor signaling contributes to sepsis induced acute kidney injury. Kidney Int. 2020;99:148–60.
Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow and function during recovery from experimental septic acute kidney injury. Intensive Care Med. 2007;33(9):1614–8.
Wan L, Langenberg C, Bellomo R, May CN. Angiotensin II in experimental hyperdynamic sepsis. Crit Care Lond Engl. 2009;13(6):R190.
Casellas D, Mimran A. Shunting in renal microvasculature of the rat: a scanning electron microscopic study of corrosion casts. Anat Rec. 1981;201(2):237–48.
Langenberg C, Gobe G, Hood S, May CN, Bellomo R. Renal histopathology during experimental septic acute kidney injury and recovery. Crit Care Med. 2014;42(1):e58-67.
Gleeson PJ, Crippa IA, Mongkolpun W, Cavicchi FZ, Van Meerhaeghe T, Brimioulle S, et al. Renin as a marker of tissue-perfusion and prognosis in critically Ill patients. Crit Care Med. 2019;47(2):152–8.
Bellomo R, Forni LG, Busse LW, McCurdy MT, Ham KR, Boldt DW, et al. Renin and survival in patients given angiotensin II for catecholamine-resistant vasodilatory shock. Am J Respir Crit Care Med. 2020;202:1253–61.
Flannery AH, Ortiz-Soriano V, Li X, Gianella FG, Toto RD, Moe OW, et al. Serum renin and major adverse kidney events in critically ill patients: a multicenter prospective study. Crit Care Lond Engl. 2021;25(1):294.
Busse LW, Schaich CL, Chappell MC, McCurdy MT, Staples EM, Ten Lohuis CC, et al. Association of active renin content with mortality in critically Ill patients: a post hoc analysis of the vitamin C, thiamine, and steroids in sepsis trial. Crit Care Med. 2023;52:441–51.
Bellomo R, Wunderink RG, Szerlip H, English SW, Busse LW, Deane AM, et al. Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock. Crit Care Lond Engl. 2020;24(1):43.
Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. Hypertens Dallas Tex 1979. 1994;23(4):439–49.
Casey L, Krieger B, Kohler J, Rice C, Oparil S, Szidon P. Decreased serum angiotensin converting enzyme in adult respiratory distress syndrome associated with sepsis: a preliminary report. Crit Care Med. 1981;9(9):651–4.
Müller AM, Gruhn KM, Herwig MC, Tsokos M. VE-cadherin and ACE: markers for sepsis in post mortem examination? Leg Med Tokyo Jpn. 2008;10(5):257–63.
Kaziani K, Vassiliou AG, Kotanidou A, Athanasiou C, Korovesi I, Glynos K, et al. Activated protein C has no effect on pulmonary capillary endothelial function in septic patients with acute respiratory distress syndrome: association of endothelial dysfunction with mortality. Infect Dis Ther. 2018;7(Suppl 1):15–25.
Krenn K, Höbart P, Poglitsch M, Croizé A, Ullrich R. Equilibrium angiotensin metabolite profiling in patients with acute respiratory distress syndrome indicates angiotensin-converting enzyme inhibition. Am J Respir Crit Care Med. 2020;202(10):1468–71.
Pode-Shakked N, Ceschia G, Rose JE, Goldstein SL, Stanski NL. Genomics of Pediatric Septic Shock Investigators. Increasing angiotensin-converting enzyme concentrations and absent angiotensin-converting enzyme activity are associated with adverse kidney outcomes in pediatric septic shock. Crit Care Lond Engl. 2023;27(1):230.
Itskovitz HD, Miller L, Ural W, Zapp J, White R. Inactivation of angiotensin in shock. Am J Physiol. 1969;216(1):5–10.
Rehfeld L, Funk E, Jha S, Macheroux P, Melander O, Bergmann A. Novel methods for the quantification of dipeptidyl peptidase 3 (DPP3) concentration and activity in human blood samples. J Appl Lab Med. 2019;3(6):943–53.
Deniau B, Blet A, Santos K, Vaittinada Ayar P, Genest M, Kästorf M, et al. Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: a proof of concept study. PLoS ONE. 2020;15(8): e0238039.
Picod A, Deniau B, Vaittinada Ayar P, Genest M, Julian N, Azibani F, et al. Alteration of the renin-angiotensin-aldosterone system in shock: role of the dipeptidyl peptidase 3. Am J Respir Crit Care Med. 2021;203(4):526–7.
Picod A, Placier S, Genest M, Callebert J, Julian N, Zalc M, et al. Circulating dipeptidyl peptidase 3 modulates systemic and renal hemodynamics through cleavage of angiotensin peptides. Hypertens Dallas Tex 1979. 2024;81:927–35.
Blet A, Deniau B, Santos K, van Lier DPT, Azibani F, Wittebole X, et al. Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study. Crit Care Lond Engl. 2021;25(1):61.
Deniau B, Picod A, Van Lier D, Vaittinada Ayar P, Santos K, Hartmann O, et al. High plasma dipeptidyl peptidase 3 levels are associated with mortality and organ failure in shock: results from the international, prospective and observational FROG-ICU cohort. Br J Anaesth. 2022;128(2):e54–7.
Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51.
Vliegen G, Kehoe K, Bracke A, De Hert E, Verkerk R, Fransen E, et al. Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2). PLoS ONE. 2020;15(4): e0231555.
Lenz M, Krychtiuk KA, Brekalo M, Draxler DF, Pavo N, Hengstenberg C, et al. Soluble neprilysin and survival in critically ill patients. ESC Heart Fail. 2022;9(2):1160–6.
Pirracchio R, Deye N, Lukaszewicz AC, Mebazaa A, Cholley B, Matéo J, et al. Impaired plasma B-type natriuretic peptide clearance in human septic shock. Crit Care Med. 2008;36(9):2542–6.
Vodovar N, Séronde MF, Laribi S, Gayat E, Lassus J, Januzzi JL, et al. Elevated plasma B-type natriuretic peptide concentrations directly inhibit circulating neprilysin activity in heart failure. JACC Heart Fail. 2015;3(8):629–36.
Lopez-Ilasaca M, Liu X, Tamura K, Dzau VJ. The angiotensin II type I receptor-associated protein, ATRAP, is a transmembrane protein and a modulator of angiotensin II signaling. Mol Biol Cell. 2003;14(12):5038–50.
Guo DF, Chenier I, Tardif V, Orlov SN, Inagami T. Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane. Biochem Biophys Res Commun. 2003;310(4):1254–65.
Nakada TA, Russell JA, Boyd JH, McLaughlin L, Nakada E, Thair SA, et al. Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock. Crit Care Med. 2011;39(7):1641–8.
Mederle K, Schweda F, Kattler V, Doblinger E, Miyata K, Höcherl K, et al. The angiotensin II AT1 receptor-associated protein Arap1 is involved in sepsis-induced hypotension. Crit Care Lond Engl. 2013;17(4):R130.
Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertens Dallas Tex 1979. 2001;38(2):177–82.
Schmidt C, Höcherl K, Kurt B, Moritz S, Kurtz A, Bucher M. Blockade of multiple but not single cytokines abrogates downregulation of angiotensin II type-I receptors and anticipates septic shock. Cytokine. 2010;49(1):30–8.
Vasques-Nóvoa F, Laundos TL, Cerqueira RJ, Quina-Rodrigues C, Soares-Dos-Reis R, Baganha F, et al. MicroRNA-155 amplifies nitric oxide/cGMP signaling and impairs vascular angiotensin II reactivity in septic shock. Crit Care Med. 2018;46(9):e945–54.
Leisman DE, Handisides DR, Busse LW, Chappell MC, Chawla LS, Filbin MR, et al. ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock. Crit Care Lond Engl. 2024;28(1):130.
Zipser RD, Davenport MW, Martin KL, Tuck ML, Warner NE, Swinney RR, et al. Hyperreninemic hypoaldosteronism in the critically ill: a new entity. J Clin Endocrinol Metab. 1981;53(4):867–73.
Findling JW, Waters VO, Raff H. The dissociation of renin and aldosterone during critical illness. J Clin Endocrinol Metab. 1987;64(3):592–5.
du Cheyron D, Lesage A, Daubin C, Ramakers M, Charbonneau P. Hyperreninemic hypoaldosteronism: a possible etiological factor of septic shock-induced acute renal failure. Intensive Care Med. 2003;29(10):1703–9.
Garcia B, Su F, Dewachter L, Favory R, Khaldi A, Moiroux-Sahraoui A, et al. Myocardial effects of angiotensin II compared to norepinephrine in an animal model of septic shock. Crit Care Lond Engl. 2022;26(1):281.
Del Greco F, Johnson DC. Clinical experience with angiotensin II in the treatment of shock. JAMA. 1961;9(178):994–9.
Derrick JR, Anderson JR, Roland BJ. Adjunctive use of a biologic pressor agent, angiotensin, in management of shock. Circulation. 1962;25:263–7.
Tumlin JA, Murugan R, Deane AM, Ostermann M, Busse LW, Ham KR, et al. Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II. Crit Care Med. 2018;46(6):949–57.
Leisman DE, Handisides DR, Chawla LS, Albertson TE, Busse LW, Boldt DW, et al. Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock. Ann Intensive Care. 2023;13(1):128.
Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care Lond Engl. 2014;18(5):534.
Chawla LS, Busse LW, Brasha-Mitchell E, Alotaibi Z. The use of angiotensin II in distributive shock. Crit Care Lond Engl. 2016;20(1):137.
Ham KR, Boldt DW, McCurdy MT, Busse LW, Favory R, Gong MN, et al. Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial. Ann Intensive Care. 2019;9(1):63.
Küllmar M, Saadat-Gilani K, Weiss R, Massoth C, Lagan A, Cortés MN, et al. Kinetic changes of plasma renin concentrations predict acute kidney injury in cardiac surgery patients. Am J Respir Crit Care Med. 2021;203(9):1119–26.
Chawla LS, Ostermann M, Forni L, Tidmarsh GF. Broad spectrum vasopressors: a new approach to the initial management of septic shock? Crit Care Lond Engl. 2019;23(1):124.
Farina N, Bixby A, Alaniz C. Angiotensin II brings more questions than answers. P T Peer-Rev J Formul Manag. 2018;43(11):685–7.
La Jolla Pharmaceutical Company. GIAPREZA (angiotensin II) package insert. 2018;
Legrand M, Bokoch MP. The Yin and Yang of the Renin-Angiotensin-Aldosterone System in Acute Kidney Injury. Am J Respir Crit Care Med. 2021;203(9):1053–5.
Chappell MC. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol. 2016;310(2):H137-152.
Nicar MJ. Specimen processing and renin activity in plasma. Clin Chem. 1992;38(4):598.
Chappell MC, Pirro NT, South AM, Gwathmey TM. Concerns on the specificity of commercial ELISAs for the measurement of angiotensin (1–7) and Angiotensin II in human plasma. Hypertens Dallas Tex 1979. 2021;77(3):e29-31.
Narumi K, Hirose T, Sato E, Mori T, Kisu K, Ishikawa M, et al. A functional (pro)renin receptor is expressed in human lymphocytes and monocytes. Am J Physiol Renal Physiol. 2015;308(5):F487-499.
Véniant M, Ménard J, Bruneval P, Morley S, Gonzales MF, Mullins J. Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest. 1996;98(9):1966–70.
Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69(1):105–13.
Leisman DE, Privratsky JR, Lehman JR, Abraham MN, Yaipan OY, Brewer MR, et al. Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model. Proc Natl Acad Sci U S A. 2022;119(34): e2211370119.
Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, et al. Angiotensin II type 2 receptor stimulation: a novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction? Circulation. 2008;118(24):2523–32.
Hollenberg NK. Implications of species difference for clinical investigation: studies on the renin-angiotensin system. Hypertens Dallas Tex 1979. 2000;35(1 Pt 2):150–4.
Rice CL, Kohler JP, Casey L, Szidon JP, Daise M, Moss GS. Angiotensin-converting enzyme (ACE) in sepsis. Circ Shock. 1983;11(1):59–63.
Jiang W, Jiang HF, Cai DY, Pan CS, Qi YF, Pang YZ, et al. Relationship between contents of adrenomedullin and distributions of neutral endopeptidase in blood and tissues of rats in septic shock. Regul Pept. 2004;118(3):199–208.
Acknowledgements
Not applicable.
Funding
The Cardiovascular Markers in Stress Conditions (MASCOT) Research Group is supported by INSERM and a research grant from 4TEEN4 Pharmaceuticals GmbH.
Author information
Authors and Affiliations
Contributions
All the authors listed meet the ICMJE authorship criteria. AP, BG, and FA drafted the manuscript, and all other authors critically reviewed the work and made substantial contribution. All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The Cardiovascular Markers in Stress Conditions (MASCOT) Research Group is supported by a research grant from 4TEEN4 Pharmaceuticals GmbH, which allowed salary support for two co-authors (AP, MG). AM received speaker’s honoraria from Abbott, Novartis, Orion, Roche, and Servier, and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, MyCartis, Neurotronik, and Sphingotec. PP received travel and consultancy reimbursement from Adrenomed, SphingoTec, 4TEEN4, AM-Pharma, Baxter, and EBI. The remaining authors have nothing to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Picod, A., Garcia, B., Van Lier, D. et al. Impaired angiotensin II signaling in septic shock. Ann. Intensive Care 14, 89 (2024). https://doi.org/10.1186/s13613-024-01325-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13613-024-01325-y