Dysregulation of renin-angiotensin-aldosterone axis in septic shock: Emerging roles of angiotensin-(1-5) and alamandine

Abstract

The renin-angiotensin-aldosterone system (RAAS) undergoes profound dysregulation during septic shock, defined by persistent hypotension requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg plus lactate > 2 mmol/L, with mortality exceeding 40%. The classical RAAS pathway becomes impaired with elevated renin but paradoxically low angiotensin (Ang) II levels, correlating with poor outcomes. The alternative Ang-converting enzyme 2-Ang-(1-7)-mas receptor axis provides counter-regulatory effects but represents a “double-edged sword” in sepsis. Elevated circulating Ang-converting enzyme 2 paradoxically predicts worse outcomes, possibly through excessive Ang II depletion contributing to vasoplegia. Downstream metabolites including Ang-(1-5) and alamandine show cardioprotective properties in experimental models. Ang-(1-5) may serve as a biomarker reflecting RAAS dysregulation severity. Elevated dipeptidyl peptidase 3 exacerbates dysfunction by degrading Ang II. Experimental Ang-(1-7) infusion prevented septic shock and reduced vasopressor requirements. However, human randomized trials remain limited. Future research should focus on biomarker-guided patient stratification and multicenter trials establishing clinical utility of alternative RAAS modulation.

Key Words: Septic shock; Sepsis; Renin-angiotensin-aldosterone system; Angiotensin-(1-7); Angiotensin-(1-5); Alamandine

Core Tip: Septic shock, as defined by sepsis-3, is a severe form of sepsis marked by high mortality, requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg and lactate > 2 mmol/L despite fluids. It involves circulatory and metabolic failure. Normally, the renin-angiotensin-aldosterone axis and sympathetic nervous system maintain vascular tone and volume. In septic shock, dysregulation occurs: Reduced angiotensin (Ang)-converting enzyme activity lowers Ang II and blunts vasoconstriction, while counter-regulatory pathways via Ang-converting enzyme 2-Ang-(1–7)-mas receptor promote vasodilation. Emerging metabolites like Ang-(1–5) and alamandine show cardioprotective roles, suggesting therapeutic potential in rebalancing renin-Ang-aldosterone signaling for refractory shock.

TO THE EDITOR

According to the Third International Consensus Definitions for Sepsis and Septic Shock, septic shock is defined as a severe and life-threatening subset of sepsis that carries particularly high mortality. Patients are classified as having septic shock when they present with the clinical picture of sepsis in association with persistent hypotension requiring vasopressor support to maintain a mean arterial pressure ≥ 65 mmHg, together with a serum lactate level > 2 mmol/L (18 mg/dL) despite adequate fluid resuscitation[1]. This definition highlights not only circulatory failure but also the underlying metabolic dysfunction, which together characterize the profound hemodynamic derangements seen in septic shock.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

To maintain circulatory stability under normal conditions, the body relies on multiple compensatory mechanisms, most notably the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. These two systems work in close coordination to regulate vascular tone, preserve effective circulating volume, and maintain electrolyte balance. In the context of septic shock, when systemic hypotension develops as a result of widespread vasodilation, capillary leak, and relative hypovolemia, these compensatory pathways are rapidly activated. The drop in blood pressure stimulates the release of renin from the juxtaglomerular cells of the kidney. This can occur directly in response to renal hypoperfusion, or indirectly via activation of β-adrenergic receptors through the sympathetic nervous system.

Renin then acts on angiotensinogen (AGT), a large glycoprotein synthesized predominantly by hepatocytes and secreted into the circulation. AGT serves as the substrate for the production of angiotensin (Ang) I. The cleavage of AGT by renin to generate Ang I is considered the rate-limiting step of the RAA cascade. Once formed, Ang I is relatively inactive, but it provides the essential precursor for the generation of Ang II.

The conversion of Ang I to Ang II is catalyzed by the Ang-converting enzyme (ACE), which is expressed in endothelial cells, particularly within the pulmonary vasculature. Ang II is the principal effector peptide of the classical RAA pathway. It exerts potent vasoconstrictor effects, thereby helping to restore systemic blood pressure. In addition, Ang II promotes aldosterone secretion from the adrenal cortex, leading to enhanced sodium and water retention in the distal nephron, ultimately expanding intravascular volume. Through these mechanisms, the ACE-Ang II-aldosterone axis contributes significantly to the restoration of hemodynamic stability and correction of electrolyte imbalances[2].

However, the RAAS is not limited to this classical pathway. An alternative or nonclassical pathway exists in which Ang I is instead metabolized by ACE2 to produce Ang-(1-7). Ang-(1-7) acts primarily on the mas receptor (MasR) and exerts effects that are, in many respects, opposite to those of Ang II. The ACE2-Ang-(1-7)-MasR axis has been shown to mediate vasodilation, anti-inflammatory activity, antifibrotic responses, and improved endothelial function, largely via stimulation of nitric oxide and prostaglandin pathways[3,4]. Thus, while the classical RAAS promotes vasoconstriction and volume retention, the alternative pathway provides a counter-regulatory mechanism that limits excessive vasoconstriction and tissue injury.

In critically ill patients, particularly in those with sepsis and septic shock, the balance between these two arms of the RAAS becomes profoundly disturbed. Several studies have demonstrated that as the severity of illness progresses, there is a decline in ACE activity and consequently lower circulating Ang II levels. Moreover, the vascular responsiveness to Ang II through its AT1 receptor is also diminished[3]. This dysregulation contributes to the persistent vasodilation and hypotension observed in refractory septic shock, and it may partly explain why conventional vasopressors sometimes fail to restore adequate perfusion pressures.

ACE2 plays a paradoxical role in sepsis, representing a “double-edged sword”. Animal studies support ACE2’s protective effects through anti-inflammatory mechanisms via Ang-(1-7) production, improving survival and reducing organ injury. However, human studies show elevated circulating ACE2 predicts worse outcomes, possibly reflecting disease severity rather than benefit. The controversy stems from distinguishing membrane-bound ACE2 (tissue-protective) from soluble ACE2 (biomarker of shedding). Additionally, excessive ACE2 activity may deplete Ang II, compromising hemodynamic stability and contributes to vasoplegia and refractory shock states.

Beyond Ang-(1-7), other downstream metabolites play emerging roles in this complex system. For example, Ang-(1-7) can be further metabolized by ACE into Ang-(1-5). Additionally, Ang-(1-7) may give rise to alamandine, a peptide that also binds to mas-related receptors. Both Ang-(1-5) and alamandine have been implicated in beneficial cardiovascular effects. Alamandine, in particular, has shown in animal models to induce endothelium-dependent vasorelaxation, confer cardioprotective benefits, and exhibit anti-inflammatory and antifibrotic properties[3,5]. These findings underscore the therapeutic potential of harnessing the nonclassical RAAS in conditions such as septic shock.

In sepsis, the alternative RAAS is activated, with ACE2 upregulation converting both Ang I and Ang II to Ang-(1-7). The increase in ACE2 activity compensates for low ACE, promoting enhanced Ang-(1-7) production even when the classical (ACE-mediated) pathway is suppressed. While Ang-(1-5) levels are often elevated in sepsis, the reduced availability of ACE in this setting impairs its efficient metabolism into alamandine. This means that despite an apparent accumulation of Ang-(1-5), the beneficial conversion to alamandine is insufficient. Consequently, Ang-(1-5) has been proposed as a potential biomarker that reflects the severity of dysregulated RAAS signaling in sepsis. Moreover, it could serve as a therapeutic target, whereby pharmacologic manipulation of this pathway might restore balance between the classical and alternative RAAS, improving vascular tone and outcomes in patients with septic shock[6]. However, more randomised control trials are required to substantiate the utility of alamandine and Ang-(1-7).

CONCLUSION

In septic shock, RAAS dysregulation with suppressed classical ACE-Ang II-aldosterone vasoconstriction and imbalanced ACE2-Ang-(1-7)-MasR counter-regulation drives refractory vasoplegia. Elevated Ang-(1-5) signals impaired alamandine production, positioning it as a biomarker of pathway imbalance. This underscores therapeutic potential in modulating nonclassical RAAS components to restore vascular tone, curb inflammation, and mitigate organ injury. Future randomized trials validating Ang-(1-7) or alamandine analogs could transform management of vasopressor-refractory shock, improving survival in this high-mortality subset of sepsis.