Induction of albuminuria in mice: Synergistic effect of two monoclonal antibodies directed to different domains of aminopeptidase A

Mentzel, S van Son, JPHF Dijkman, HBPM Wetzels, JFM Assmann, KJM

S. Mentzel et al., Induction of albuminuria in mice: Synergistic effect of two monoclonal antibodies directed to different domains of aminopeptidase A, KIDNEY INT, 55(4), 1999, pp. 1335-1347

54

INGLESE

Article

Urology & Nephrology","da verificare

KIDNEY INTERNATIONAL

0085-2538 → ACNP

55

4

1999

1335 - 1347

ISI

0085-2538(199904)55:4<1335:IOAIMS>2.0.ZU;2-X

Background. Aminopeptidase A is an enzyme that is present on podocytes and is involved in the degradation of angiotensin II. In previous studies in mi ce, we administered single monoclonal antibodies directed against aminopept idase A. We observed that only monoclonal antibodies that inhibited aminope ptidase A enzyme activity caused albuminuria. Methods. In this study, the effects of the combined injections of two monoc lonal anti-aminopeptidase A antibodies (mAbs) were studied, using a combina tion of anti-aminopeptidase A mAbs that were directed against two different domains involved in the aminopeptidase A enzyme activity (ASD-3 or ASD-37) and an anti-aminopeptidase A mAb not related to the enzyme active site (AS D-41). Results. An injection of the combinations ASD-3/37 (total 4 mg, 1:1 ratio) and ASD-37/41 (total 4 mg, 1:1 ratio) in doses that do not cause albuminuri a when given alone (4 mg) induced massive albuminuria at day 1 after inject ion. The combination ASD-3/41 had no effect. This albuminuria was not depen dent on systemic immune mediators of inflammation and could not merely be r elated to a blockade of aminopeptidase A enzyme activity. However, a correl ation was observed between the induction of albuminuria and the aggregation of the mAbs injected and aminopeptidase A on the podocytes. An injection o f the combinations ASD-3/37 or ASD-37/41 did not cause an increase in syste mic blood pressure. The treatment with a combination of enalapril and losar tan lowered blood pressure (53 +/- 10 vs. 90 +/- 3 mm Hg in untreated mice) and reduced the acute albuminuria by 55% (11,145 +/- 864 vs. 24,517 +/- 24 48 mu g albumin/18 hr in untreated mice). However, similar effects were obs erved using triple therapy. Therefore, the reduction of albuminuria by the combined treatment of enalapril/losartan seems to be the consequence of the reduction in the systemic blood pressure. These findings argue against a s pecific role for angiotensin II in this model. Conclusions. The combined injection of two mAbs directed against different domains of aminopeptidase A induces a massive albuminuria in mice, which is not merely dependent on angiotensin II. We hypothesize that the direct bin ding of mAbs to at least two pathogenic domains on aminopeptidase A trigger s the podocyte to release mediators that are involved in the observed album inuria.