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The Novel Angiotensin-Converting Enzyme (ACE) Homolog, ACE2, Is Selectively Expressed by Adult Leydig Cells of the Testis

Baker Heart Research Institute (G.C.D., D.K.L.L., M.A.Y., A.I.S., R.A.L.), Melbourne 8008; Monash University Institute of Reproduction and Development (G.C.D., M.K.O., M.P.H.), Clayton 3168; and the Australian Research Council Centre of Excellence in Biotechnology and Development (M.K.O.), Canberra 2601, Australia

Address all correspondence and requests for reprints to: A. Ian Smith, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. E-mail: ian.smith{at}med.monash.edu.au.

The metallopeptidase angiotensin-converting enzyme (ACE) plays a pivotal role in the cardiovascular system by generating the vasoconstrictor peptide angiotensin II. A homolog of ACE with different substrate specificity, ACE2, has recently been cloned that shows an expression pattern restricted to endothelial cells of the heart and kidney, epithelial cells of the distal tubule of the kidney, and the testis. Although the importance of ACE2 to cardiac function is already evident, its role in the testis remains unknown. In this study, we report the cloning and expression of human testicular ACE2 and confirm that it is identical to the somatic form of the enzyme. ACE2 catalytic activity was present in membrane preparations of whole testes and Leydig cells from adult rats; expression of the protein in Leydig cells was confirmed by Western immunoblot analysis. Using immunohistochemistry, ACE2 expression was confined to the Leydig cells in the rat testis and to Leydig and Sertoli cells in the human testis. Ablation of the Leydig cells in the rat by the specific toxin, ethane dimethane sulfonate, eliminated ACE2-positive cells from the interstitium. Expression of ACE2 in rat Leydig cells was up-regulated during the development of adult-type Leydig cells at puberty and after ethane dimethane sulfonate treatment. Expression of ACE2 activity in the testis was not significantly altered by manipulation of the pituitary-testicular hormonal axis with sc testosterone implants. These data suggest that ACE2 is a constitutive product of adult-type Leydig cells and may participate in the control of testicular function by as yet unknown mechanisms.

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