ACE2/Angiotensin 1-7 protective anti-inflammatory and antioxidant role in hyperoxic lung injury: support from studies in Bartter’s and Gitelman’s syndromes

Abstract

Using an animal model of hyperoxic lung injury, Fang et al.1 have shown that ACE2/Angiotensin (Ang) 1–7 system plays an important anti-inflammatory and antioxidant role protecting the lungs from the hyperoxic injury via the inhibition of the NF-κB pathway and activation of Nrf2/HO-1/NQO1 pathway. We feel that our extensive studies in Bartter’s and Gitelman’s syndrome (BS/GS) patients may provide further support in humans to Fang et al. demonstration obtained in an animal model. Bartter’s and Gitelman’s syndromes are rare diseases caused by gene defects in specific kidney transporters and ion channels, characterized by the activation of the renin–angiotensin–aldosterone system, high Ang II and aldosterone, yet normotension or hypotension, hyporesponsiveness to pressors, activation of anti-atherosclerotic and antiremodeling defenses, reduction of oxidative stress and inflammation, representing a human model opposite to hypertension.2 Particular relevance for the antioxidant and anti-inflammatory role of ACE2/Ang 1-7 axis is the demonstration in BS/GS of increased levels of both ACE2 and Ang 1-7 which were directly correlated, compared to hypertensive patients and healthy subjects.2,3 Moreover, these patients have increased HO-1 expression,2 potent antioxidant and anti-inflammatory agent, whose increase may represent the upregulation of Nrf2/HO-1/NQO1 pathway mediated by the ACE2 induced inhibition of NF-κB pathway, as shown by Fang et al.1 This is true also for BS/GS patients who have reduced activity of NF-κB and reduced NF-κB mediated transcription of regulated genes, which are involved in inflammation and remodeling as IκB, the inhibitory subunit of NFκB, is increased and inflammatory cytokine production is reduced.2,3 Moreover, particularly relevant in relation to Fang et al. study, is also the downregulation of RhoA/Rho kinase (ROCK) pathway in BS/GS.2 This pathway in addition to be deeply involved in changes of vascular tone and structure leading to hypertension and cardiovascular-renal remodeling also via induction of oxidative stress,2 has a relevant role in the induction of lung fibrosis, on which ACE2 and Ang 1-7 infusion were shown, in an animal model, to be protective via downregulation of RhoA/ROCK pathway.4 In conclusion, the increased ACE2, Ang 1-7 and HO-1 level, the downregulation of NF-κB and RhoA/ROCK pathway with reduction of oxidative stress and inflammation shown in BS/GS patients2,5 strongly support the data obtained by Fang et al. in an animal model1 and exhibit a mirror image of that resulting by the ROCK induced pulmonary fibrosis.4 Our data in humans jointed with those provided by Fang et al. in animals encourage future works with clinical trials examining the levels and effects of ACE2/Ang 1-7 in hyperoxic lung injury. Conflict of interest. None declared.