INHIBITION OF AMINOPEPTIDASE-A ACTIVITY CAUSES AN ACUTE ALBUMINURIA IN MICE - AN ANGIOTENSIN II-MEDIATED EFFECT

The hydrolase aminopeptidase A is an important regulator of the renin- angiotensin system, since it inactivates its most vasoactive component angiotensin II (Ang II). A single i.v. injection of a monoclonal anti body against mouse aminopeptidase A (ASD-4) induces a membranous-like glomerulonephritis in mice, characterized by an acute albuminuria, tha t is not dependent on complement, the coagulation system, or inflammat ory cells. We hypothesized that this albuminuria is the consequence of a reduction in aminopeptidase A enzyme activity, that might subsequen tly lead to an increase in Ang II levels. Aminopeptidase A enzyme acti vity was analysed in vitro :by a fluorimetric enzyme assay and in vivo by enzyme histochemistry. The role of Ang II in the induction of albu minuria in this model was studied by measuring the renal aminopeptidas e A mRNA expression in our model by a competitive PCR assay as an indi rect measure of Ang II levels. In addition, the role of Ang II in this model was studied by preventing the formation of Ang II with the angi otensin-converting enzyme inhibitor enalapril or by blocking of the An g II receptor with the AT1 receptor antagonist losartan. Only antibodi es that were able to inhibit the aminopeptidase A enzyme activity in v itro and in vivo induced an acute albuminuria in mice. Renal aminopept idase A mRNA expression was increased by injection of the anti-aminope ptidase A antibody. Both enalapril and losartan treatment reduced the acute albuminuria, measured 1 day after injection of a monoclonal anti body against aminopeptidase A, by 91% and 83%, respectively. It is con cluded that the induction of acute albuminuria is correlated to the en zyme-inhibiting capacity of the anti-aminopeptidase A antibodies. This impaired enzymatic activity most likely leads to an increase in the l evels of Ang II, the best known substrate of aminopeptidase A. The res ults of our additional experiments are in keeping with our hypothesis that Ang II mediates this acute albuminuria. Whether this occurs by an increase of blood pressure or by a growth factor-like effect remains to be defined by further studies in this model.