Reversible activation–inactivation of renin in human plasma

Abstract

Renin, an aspartate protease, cleaves the α-globulin angioten-sinogen to produce the decapeptide angiotensin I, which is then converted to the vasoactive hormone angiotensin II by the action of a peptidase ‘converting enzyme’. An inactive form of renin^1–3 sometimes termed prorenin⁴ is present in normal human plasma. Its enzymatic activity is increased by exposure to a pH of 3.0 or 3.3 followed by dialysis towards neutral pH. Only a small proportion of the inactive renin is activated during the acid stage of dialysis, most of the activation apparently taking place during the subsequent dialysis to pH 5.7 (ref. 4) or 7.5 (ref. 5). Furthermore, if inhibitors of serine proteases are added to the plasma, the amount of inactive renin activated by this dialysis procedure is reduced^4–6. These results suggest that acid-activation is mediated by serine proteases. The role of enzymes such as plasma kallikrein, plasmin and renal kallikrein as physiological activators of inactive renin has recently been discussed^5–9. In our study of the activation of plasma inactive renin we have now found that, contrary to previous reports^4,5, complete activation of inactive renin takes place during the acid stage of dialysis. This activation can be reversed if plasma is rapidly adjusted to pH 7.4 and warmed. The next step in the acid-activation procedure, that is, dialysis to neutral pH, renders the initial acid-activation irreversible. These results were completely unexpected, and we offer an explanation that reassesses the nature of inactive renin and the activation process.