Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

Wysocki, Jan; Schulze, Arndt; Batlle, Daniel

ACE2 is a tissue enzyme with low levels of activity in plasma [13, 17] . In urine, enzymatic ACE2 activity is substantial [12, 18, 19] . Two distinctive ACE2-specific bands have been reported in mice and human urine [18] [19] [20] [21] . One ACE2-immunoreactive band, at about 100-110 kD, corresponds to the expected molecular weight of native ACE2 at 110 kD [12] . This 100-110 kD ACE2-immunoreactive band is likely the result of shedding from the kidney apical tubular membrane, where ACE2 protein is abundantly expressed [22] [23] [24] . The other ACE2-imunoractive band detectable in mouse urine is of a lower size (~75 kD) and its origin and whether or not it is active remains unclear [12] . Based on these observations, we hypothesized that ACE2 variants of a shorter molecular size could be generated and still retain enzymatic activity. Accordingly, we sought to develop short ACE2 variants small enough, so that they could be filtered and subsequently re-absorbed by the kidney tubules. The kidney uptake of these small ACE2 variants, in turn, would foster Ang (1-7) formation from Ang II, thereby providing a novel and direct approach to target the kidney RAS, which is overactive in some forms of kidney disease, including acute kidney injury.