A MUTATION OF ANGIOTENSINOGEN IN A PATIENT WITH PREECLAMPSIA LEADS TO ALTERED KINETICS OF THE RENIN-ANGIOTENSIN SYSTEM

Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues, In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in K-m (from 1.1 to 0.09 mu M) and a 5-fold decrease in k(cat) (from 1.0 to 0.22 s(-1)); as a result, catalytic efficiency (k(cat)/K-m) is increased by a factor of 2 (1.1 versus 2.4 mu M(-1) s(-1)). In the reaction of angiotensin converting enzyme on angiotensin decapeptides, the substitution has no effect on K-m (38.0 versus 30.0 mu M), but increases k(cat) and catalytic efficiency >2-fold (k(cat) = 15.0 versus 37.0 s(-1); k(cat)/K-m = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.