Angiotensin converting enzyme (ACE) is responsible for the conversion of angiotensin I into the potent vasoconstrictor angiotensin II. As early as 1971, researchers were surprised to find that testis contains large amounts of ACE, and that the protein found in this tissue was biochemically distinct from the ACE enzyme produced by endothelium and other somatic tissues. Subsequent analysis has demonstrated that developing male germ cells produce large amounts of ACE mRNA encoding a protein approximately half as large as that observed in somatic tissues. Despite the smaller size, testis ACE is fully catalytic. Within all mammals studied to date, the ACE gene is encoded by a single genetic locus. Developing germ cells are unique in that they begin mRNA transcription of ACE within the 12th intron of the somatic ACE gene. Transgenic mouse studies have demonstrated that a very small portion of DNA located within this 12th intron serves as a male germ cell specific promoter for testis ACE transcription. From this and other studies, it is clear that testis ACE transcription is truly tissue restricted and reflects the unique biochemistry within developing male germ cells. The first Specific Aim is to define the biochemistry of testis ACE promoter transcription and to characterize and clone the male germ cell transcription factors that lead to high level ACE transcription. One of the most important and least understood questions concerning testis ACE is the role of this protein in male germ cell development. There is evidence both for and against the view that testis ACE is functionally important. However, in my opinion the data are inconclusive in establishing whether ACE plays an important role in spermatogenesis or in some aspect of fertilization. We believe the only definitive way to investigate the role of testis ACE is to create mice, using the technique of targeted homologous recombination, that completely lack testis ACE. Thus the second Specific Aim of the proposal is to use targeted homologous recombination to generate mice that do not produce testis ACE. This will permit study of the role of testis ACE during male germ cell development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051445-02
Application #
2414932
Study Section
Reproductive Biology Study Section (REB)
Project Start
1996-05-01
Project End
2000-04-30
Budget Start
1997-05-15
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Giani, Jorge F; Eriguchi, Masahiro; Bernstein, Ellen A et al. (2017) Renal tubular angiotensin converting enzyme isĀ responsible for nitro-L-arginine methyl esterĀ (L-NAME)-induced salt sensitivity. Kidney Int 91:856-867
Shen, Xiao Z; Ong, Frank S; Bernstein, Ellen A et al. (2012) Nontraditional roles of angiotensin-converting enzyme. Hypertension 59:763-8
Lin, Chentao; Datta, Vivekanand; Okwan-Duodu, Derick et al. (2011) Angiotensin-converting enzyme is required for normal myelopoiesis. FASEB J 25:1145-55
Gonzalez-Villalobos, Romer A; Billet, Sandrine; Kim, Catherine et al. (2011) Intrarenal angiotensin-converting enzyme induces hypertension in response to angiotensin I infusion. J Am Soc Nephrol 22:449-59
Silberman, Gad A; Fan, Tai-Hwang M; Liu, Hong et al. (2010) Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation 121:519-28
Weiss, Daiana; Bernstein, Kenneth E; Fuchs, Sebastian et al. (2010) Vascular wall ACE is not required for atherogenesis in ApoE(-/-) mice. Atherosclerosis 209:352-8
Li, Ping; Xiao, Hong D; Xu, Jianguo et al. (2010) Angiotensin-converting enzyme N-terminal inactivation alleviates bleomycin-induced lung injury. Am J Pathol 177:1113-21
Okwan-Duodu, Derick; Datta, Vivekanand; Shen, Xiao Z et al. (2010) Angiotensin-converting enzyme overexpression in mouse myelomonocytic cells augments resistance to Listeria and methicillin-resistant Staphylococcus aureus. J Biol Chem 285:39051-60
Campbell, Duncan J; Xiao, Hong D; Fuchs, Sebastien et al. (2009) Genetic models provide unique insight into angiotensin and bradykinin peptides in the extravascular compartment of the heart in vivo. Clin Exp Pharmacol Physiol 36:547-53
Shen, Xiao Z; Xiao, Hong D; Li, Ping et al. (2008) Tissue specific expression of angiotensin converting enzyme: a new way to study an old friend. Int Immunopharmacol 8:171-6

Showing the most recent 10 out of 38 publications