THE CRITICAL ROLE OF TISSUE ANGIOTENSIN-CONVERTING ENZYME AS REVEALEDBY GENE TARGETING IN MICE

Angiotensin-converting enzyme (ACE) generates the vasoconstrictor angi otensin II, which plays a critical role in maintenance of blood pressu re in mammals. Although significant ACE activity is found in plasma, t he majority of the enzyme is bound to tissues such as the vascular end othelium. We used targeted homologous recombination to create mice exp ressing a form of ACE that lacks the COOH-terminal half of the molecul e. This modified ACE protein is catalytically active but entirely secr eted from cells. Mice that express only this modified ACE have signifi cant plasma ACE activity but no tissue-bound enzyme. These animals hav e low blood pressure, renal vascular thickening, and a urine concentra ting defect. The phenotype is very similar to that of completely ACE-d eficient mice previously reported, except that the renal pathology is less severe. These studies strongly support the concept that the tissu e-bound ACE is essential to the control of blood pressure and the stru cture and function of the kidney.