Table 1 Therapies targeting the alternative renin–angiotensin system
Therapies targeting the alternative renin–angiotensin system | |||
|---|---|---|---|
Preclinical studies | |||
Study | Model | Main findings | |
rhACE2 | Imai et al. 2005 | Acid-induced acute lung injury in mice | Recombinant human ACE2 reduced changes in elastance observed in the lung and wet to dry ratio induced by acid injury |
Angiotensin-(1–7) | Zhu et al. 2021 | LPS in mice | Ang-(1–7) administered for 15 days, followed by an LPS challenge, resulted in reduced increase in TNF-α, IL-1, and IL-6 in both serum and kidney compared to the LPS group, and to reduced levels of urea, creatinine, and cystatin C |
Tsai et al. 2018 | CLP in rat | Administration of Ang-(1–7) at a dosage of 1 mg/kg at 3 and 6 h after CLP led to a reduced increase in IL-6, improved mean arterial pressure, and enhanced organ function, as evidenced by liver and renal biomarkers. Additionally, survival rates improved from 36.4% to 83.3% at 24 h (p < 0.01) | |
Garcia et al. 2023 | Polymicrobial peritonitis in sheep | Ang-(1–7) started at sepsis induction prevented the development of septic shock, with 6 out of 7 animals maintaining normal arterial lactate levels at 24 h. Ang-(1–7) reduced norepinephrine requirements and prevented renal dysfunction. Additionally, there was a reduction in the increase of IL-6, associated with a trend toward improved survival rates. In the control group, 2 out of 7 animals died before 24 h, while all 7 animals in the treated group survived | |
Zambelli et al. 2015 | Acid-induced acute lung injury in rats | High doses of Ang-(1–7) improved oxygenation, reduced white blood cells counts and reduced inflammatory cell numbers in bronchoalveolar lavage | |
AT2 agonist | Fatima et al. 2021 | LPS in mice | A single dose of C21, an agonist of AT2, resulted in an increase in the circulating anti-inflammatory cytokine IL-10 and a reduction in the biomarkers of AKI, NGAL and KIM1 |
Shih et al. 2023 | CLP in rats | CGP42112 three hours after the CLP procedure mitigated hypotension, led to a reduction in the increase of biomarkers for liver and renal injury, and improved survival rates from 20 to 50% at 24 h (p < 0.05) | |
DPP3 inhibition | Deniau et al. 2020 | CLP in rats | Procizumab, a humanized antibody that neutralizes DPP3 activity, administered 16 h after CLP, restored systolic dysfunction from 39 to 51% within 30 min. It also reduced oxidative stress in the heart and improved survival rates from 63 to 83% (p = 0.0026) at 120 min after randomization |
Clinical studies | |||
Study | Patients | Main findings | |
rhACE2 | Zoufaly et al. 2020 | 45 years old woman with severe COVID19 | rhACE2 was started 9 days after symptoms onset twice daily and resulted in reduction in circulating Ang II levels and increase in Ang-(1–7), Ang-(1–9) and Ang-(1–5) |
NCT04335136 | 181 hospitalized patients for COVID19 | The primary endpoint was a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge. No differences were reported in the primary outcome | |
Angiotensin-(1–7) | Martins et al. 2021 | 28 patients admitted to the ICU | Ang-(1–7) was administrated intravenously for up to 7 days. No changes in hemodynamic parameters were observed. Bradycardia was observed in one patient |
Self et al. 2023 | 343 patients with hypoxemia | Patients were randomized to receive daily either 0.5 mg/kg of angiotensin-(1–7) for 5 days or placebo. Oxygen-free days did not differ between the groups at day 28 (mean difference − 2.3 days [95% CrI, − 4.8 to 0.2] | |