Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.
Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Saurabh
S
Chattopadhyay
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Sean P
SP
Kessler
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Juliana Almada
JA
Colucci
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Michifumi
M
Yamashita
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Preenie deS
Pd
Senanayake
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Ganes C
GC
Sen
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015139:Blotting, Southern; D003404:Creatinine / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood
D000804:Angiotensin II; D003404:Creatinine; D007703:Peptidyl-Dipeptidase A; D012083:Renin