Previous studies using XNT have suggested that the molecule has a unique role as a hypotensive and antifibrotic agent within the RAS acting primarily as an activator of the ACE2. In this study, we assessed the hypothesis that XNT attenuates hypertension by an ACE2-independent mechanism.
Studies were performed in C57BL6 WT and ACE2KO mice. BP was monitored continuously for a period of 25 min following a bolus of Ang II infusion after either XNT or recombinant (r)ACE2 was administered.
Ang peptides were examined in plasma ex-vivo using MAS spectrometry analysis (RAS-fingerprint). ACE2 activity in serum was measured after XNT and/or Ang II infusion, in order to investigate a potential effect of XNT on serum ACE2.
With regard to blood pressure, both XNT (n=11) and rACE2 (n=11) were able to markedly attenuate Ang II -induced hypertension in WT mice. However, a similar decline in BP caused by XNT was also seen in ACE2KO mice (n=14), indicating that the BP-lowering effect of XNT was ACE2-independent. This was additionally evidenced by serum ACE2 activity measurements in WT mice performed 5 minutes after Ang II infusion, showing no significant variation between XNT (0.351±0.06 RFU/ul/hr) and control group (0.393±0.04 RFU/ul/hr). Moreover, results from MAS spectrometry analysis showed that the presence of XNT did not alter plasma Ang II, Ang (1-7) or Ang (1-5) levels, whereas rACE2, without XNT addition, significantly increased Ang (1-7) and Ang(1-5) levels as a result of enhanced Ang II degradation.
XNT has a potent BP-lowering effect in AngII-dependent hypertension but this action is ACE2-independent and unrelated to Ang II or Ang (1-7).