Original Research ArticleBML-111 equilibrated ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis to protect hepatic fibrosis in rats

- Lipoxins (LXs), endogenously produced eicosanoids, have been approved for potent anti-inflammatory and pro-resolving properties.Recently, it was reported LXs had protective effects on fibrous diseases, and RAAS played vitally bidirectional roles in hepatic fibrosis through ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis. But the complicated mechanisms of anti-fibrosis of LXs remain unclear.Furthermore, Both LXs and RAAS could regulate fibrosis, inflammatory response, oxidative stress, and cell proliferation.It seemed the biological effects of RAAS and LXs are much similar. More importantly, it was reported Lipoxin A4 could regulated the sodium channel and Na+/K+-ATPase activity, which suggested that LXs could regulate the channels and concentrations of Na+.It is well known the concentrations of Na+ is the root reason to change the expression levels of renin, which is one of the main components of RAAS and is the direct cause for induction of all kind of angiotensins.However, the relations of RAAS and LXs are not explored also. In this study, a rat model of carbon tetrachloride (CCL4)-induced hepatic fibrosis was used to observe the relations of RAAS and LXs, and to explore the alternative anti-fibrosis mechanisms of LXs.
- We demonstrated that BML-111, a lipoxin receptor agonist, played a critical protective role in CCL4-induced hepatic fibrosis through equilibrating ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis in rats.
- LXs and the analogs might be potential agents against hepatic diseases, and the novel adjusted target might be RAAS.

BackgroundIt was recently reported Lipoxins (LXs) had protective effects on fibrous diseases, and renin-angiotensin-aldosterone system (RAAS) had played vital and bidirectional roles in hepatic fibrosis. In this paper, a hepatic fibrosis model, induced by carbon tetrachloride (CCL4) in rats, was used to observe the relations between RAAS and LXs, as well as to further explore the alternative anti-fibrosis mechanisms of LXs.MethodsThe model was evaluated by morphological observations and biochemical assays. The activities and contents of angiotensin converting enzyme (ACE) and angiotensin converting enzyme 2 (ACE2) were examined through assay kits and ELISA. The expression levels of angiotensinII (AngII), Angiotensin II type 1 receptor (AT1R), angiotensin-(1-7) (Ang-1-7), and Mas were all measured using real time PCR, ELISA, and Western blot.ResultsThe model was established successfully and BML-111 significantly ameliorated CCL4-induced hepatic fibrosis, including reduction inflammation injury, decrease extracellular matrix deposition, and improvement hepatic functions. Furthermore, BML-111 could obviously decrease not only the activities of ACE but also the expression levels of ACE, AngII,and AT1R, which were induced by CCL4. On the other hand, BML-111 could markedly increase the activities of ACE2, besides the expression levels of ACE2, Ang-(1-7) and Mas. More importantly, BOC-2, a lipoxin A4 receptor blocker, could reverse all these phenomena.ConclusionsEquilibrating ACE-AngII-AT1R axis and ACE2-Ang-(1-7)-Mas axis mediated the protective effect of BML-111 on hepatic fibrosis in rats.