Role of Intrinsic Inhibitors in Acid-Activation of Inactive Plasma Renin (Prorenin)

Inactive plasma renin is converted into an active form of renin during dialysis of plasma against a pH 3.3-buffer. This form of renin is inactivated at neutral pH. When plasma, after acid-dialysis, is kept at neutral pH a different form of active renin is generated, which remains active. The irreversible activation of prorenin depends on factor XII-initiated kallikrein formation. C1-inhibitor (C1-INH) and α2-macroglobulin (α2M) can be selectively denaturated by treatment of plasma at low pH values to which kallikrein and renin are resistant. After denaturation of C1-INH at pH 4-5, factor XII becomes capable of activating prekallikrein. The kallikrein that is formed after restoration of pH is complexed with α2M. This complex has little activity towards natural protein substrates including prorenin. α2M is denaturated at pH 3-4 and, as a consequence, kallikrein that is formed after restoration of pH is not complexed with α2M. This kallikrein is able to attack both high-molecular weight kininogen and prorenin as manifested by the generation of bradykinin-forming and angiotensin-forming activities. These observations show a crucial role for C1-INH and α2M in prorenin activation and explain, at least in part, why the pH of the acid-treatment step has to be less than 4 before irreversible activation of prorenin at neutral pH can occur.