Reply to Picod et al.: Alteration of the Renin–Angiotensin–Aldosterone System in Shock: Role of the Dipeptidyl Peptidase 3

From the Authors:

We thank Picod and colleagues for their comments about our manuscript (1). The renin–angiotensin–aldosterone system (RAAS) is disordered in patients with catecholamine-resistant vasodilatory shock (CRVS). Thus, we have described the RAAS Disturbance Hypothesis, which postulates that there is inadequate activation of the ATR1 (angiotensin type I receptor) in some patients with CRVS. In our study, we demonstrated that elevated renin levels are common in patients with CRVS and that the renin levels correlate with the angiotensin I/angiotensin II ratio, which is also elevated (1). We reasoned that ACE (angiotensin-converting enzyme) dysfunction was the most likely cause for these findings. This hypothesis is bolstered by our findings that the exogenous administration of angiotensin II resulted in a rapid decrease in both renin and angiotensin I levels compared with placebo. Picod and colleagues rightly point out that increased angiotensin II degradation by neutral endopeptidase offers an additional explanation for our findings. We agree that this is important and that further research into the nature and cause of angiotensin II insufficiency and the role of both classical and nonclassical enzymes (ACE, ACE2, and/or neutral endopeptidase) in the generation and degradation of the different major angiotensins identified so far (especially angiotensin I, angiotensin II, angiotensin 1-7, angiotensin 1-9, and angiotensin 15) is warranted.

The consequences of RAAS disturbance in CRVS are broad and impact multiple organs. Preclinical studies confirm early findings by Wan and colleagues that adequate ATR1 engagement is critical for renal function (2). Recently, Leisman and colleagues demonstrated that impaired ATR1 signaling contributes to sepsis-induced acute kidney injury (AKI) (3). In this study, administration of angiotensin II was found to attenuate AKI whereas the administration of losartan exacerbated AKI. The focus on renal function is obvious, but the ATR1 receptor also has important cardiac function. The ATR1 receptor has dual signaling via G protein–coupled receptor and the β-arrestin pathway. In addition, β-arrestin modulates internalization of the receptor and the inotropic properties of angiotensin II (4, 5).

In summary, at a clinical level, RAAS disturbances in CRVS may be identified by serum renin measurement, which is an inexpensive and widely available test. Elevated renin levels may represent a bio-type of CRVS, which can be treated with RAAS-modulating agents to improve patient-centered outcomes including survival. At a biological level, the journey to understand the extraordinary complexity of the nonclassical RAAS pathways has just begun.