Mechanism of acid-activation of renin: role of kallikrein in renin activation.
Dialysis of plasma in pH 3.3 and then pH 7.5 is a method commonly used to activate plasma inactive renin. Endogenous plasma kallikrein has been shown to participate in activation during neutral dialysis. The present studies demonstrate that plasma inactive renin is fully activated following dialysis to pH 3.3 at 10 degrees C. Activation by low pH is a reversible process when followed by titration to a pH greater than 4.0. The rate of reversal of acid activation increases with increasing pH and temperature, reaching a maximum at pH 7.0 ad 37 degrees C. the disappearance of activated renin is not due to its destruction, because dialysis back to pH 3.3 fully restores activation. A preparation of renin zymogen devoid of active renin also shows complete reversal of activation. The Km of acid-activated renin is the same as that of endogenous active renin. Acid-activated renin (untreated by protease) elutes with an apparently greater Stokes radius than non-acid-treated inactive renin on Sephadex G-100. Once reversal of acid activation occurs, renal or plasma kallikrein has no effect on renin. However, once kallikrein acts on acid-activated renin, activation is no longer reversible. These data can explain the mechanism of acid activation of renin and the contribution of plasma kallikrein to renin activation in vitro. At low pH, inactive renin appears to undergo a conformational change such that the active site is accessible. Acid may unfold the renin molecule, as suggested by an increase in Stokes radius following acid dialysis. Kallikrein may then cleave a small peptide that permanently maintains acid-activated renin in an active state. Thus, renin zymogen must be in an active conformation such as that induced by acid to be "acted upon" by kallikrein, suggesting that other factors, in addition to renal kallikrein, may be involved in renin activation in vivo.
D000143:Acids / Q000494:pharmacology; D000803:Angiotensin I / Q000096:biosynthesis; D002850:Chromatography, Gel; D003956:Dialysis; D004789:Enzyme Activation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007610:Kallikreins / Q000502:physiology*; D008970:Molecular Weight; D012083:Renin / Q000378:metabolism*
D000143:Acids; D000803:Angiotensin I; D007610:Kallikreins; D012083:Renin