Th e current fi ndings are of potential importance in our understanding of the role of circulating and tissue sources of ACE2, particularly in various disease states. Increased circulating levels of ACE2 may refl ect a compensatory mechanism to alter the balance of the renin-angiotensin system to favor the ACE2-Ang-(1-7)-AT 7 receptor axis and promote the antifi brotic and anti-infl ammatory actions of the heptapeptide, as well as attenuate the Ang II-AT 1 receptor pathway. Clearly, generation of endogenous antibodies with inhibitory activity against ACE2 may undermine this compensatory response. Indeed, identifi cation of endo genous ACE2 inhibitors is important in lieu of optimizing the therapeutic benefi ts following administration of recombinant soluble ACE2, as recently demonstrated in models of diabetic nephropathy [8] and liver fi brosis [9] or in the genetic expression of ACE2 in pulmonary hypertension [10] .