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J. Biol. Chem., Vol. 280, Issue 47, 39353-39362, November 25, 2005

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Angiotensin-converting Enzyme 2 (ACE2), But Not ACE, Is Preferentially Localized to the Apical Surface of Polarized Kidney Cells^*

Fiona J. Warner1, Rebecca A. Lew, A. Ian Smith, Daniel W. Lambert, Nigel M. Hooper, and Anthony J. Turner2

From the Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom and the Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia

Angiotensin-converting enzyme-2 (ACE2) is a homologue of angiotensin-I converting enzyme (ACE), the central enzyme of the renin-angiotensin system (RAS). ACE2 is abundant in human kidney and heart and has been implicated in renal and cardiac function through its ability to hydrolyze Angiotensin II. Although ACE2 and ACE are both type I integral membrane proteins and share 61% protein sequence similarity, they display distinct modes of enzyme action and tissue distribution. This study characterized ACE2 at the plasma membrane of non-polarized Chinese hamster ovary (CHO) cells and polarized Madin-Darby canine kidney (MDCKII) epithelial cells and compared its cellular localization to its related enzyme, ACE, using indirect immunofluorescence, cell-surface biotinylation, Western analysis, and enzyme activity assays. This study shows ACE2 and ACE are both cell-surface proteins distributed evenly to detergent-soluble regions of the plasma membrane in CHO cells. However, in polarized MDCKII cells under steady-state conditions the two enzymes are differentially expressed. ACE2 is localized predominantly to the apical surface (92%) where it is proteolytically cleaved within its ectodomain to release a soluble form. Comparatively, ACE is present on both the apical (55%) and basolateral membranes (45%) where it is also secreted but differentially; the ectodomain cleavage of ACE is 2.5-fold greater from the apical surface than the basolateral surface. These studies suggest that both ACE2 and ACE are ectoenzymes that have distinct localization and secretion patterns that determine their role on the cell surface in kidney epithelium and in urine.

Received for publication, August 12, 2005

^* This work was supported in part by grants from the British Heart Foundation and the U.K. Medical Research Council (to A. J. T. and N. M. H.) and the Wellcome Trust (University of Leeds Bioimaging Suite). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a C. J. Martin Research Fellowship awarded by the National Health and Medical Research Council (Australia).

² To whom correspondence should be addressed. Tel.: 44-113-343-3131; Fax: 44-113-242-3187; E-mail: a.j.turner{at}leeds.ac.uk.

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