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Nephron Function in Transgenic Mice with Selective Vascular or Tubular Expression of Angiotensin-Converting Enzyme

Sean P. Kessler^*, Seiji Hashimoto, Preenie S. Senanayake, Christina Gaughan^*, Ganes C. Sen^* and Jurgen Schnermann

^* Department of Molecular Genetics, Lerner Research Institute, and Department of Ophthalmic Research, Cleveland Clinic Foundation, Cleveland, Ohio; and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Address correspondence to: Dr. Sean P. Kessler, Department of Molecular Genetics NE20, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-444-0884; Fax: 216-444-0512; kessles{at}ccf.org

Received for publication February 8, 2005. Accepted for publication August 24, 2005.

Angiotensin-converting enzyme (ACE) null mice display aberrant renal pathology. Inadequate formation of angiotensin II (Ang II) results in hypotension, loss of fluid homeostasis, lack of urine concentration, and failure to regulate GFR through the tubuloglomerular feedback (TGF) mechanism. For examining the tissue-specific role of ACE in renal structure and regulation of renal filtrate formation, single-nephron GFR, proximal tubular fluid reabsorption, and TGF responsiveness were determined in mice that expressed ACE in only one tissue. Maximum TGF responses in mice that expressed somatic ACE (sACE) in proximal tubule cells (Gs strain) or germinal ACE in the serum (Pg strain) were reduced significantly compared with wild-type (WT) mice. In contrast, TGF responses in mice that expressed sACE in vascular endothelial cells (Ts strain) were not different from control. Single-nephron GFR was reduced in Ts compared with WT mice, but fractional reabsorption and therefore glomerulotubular balance were not distinguishable. BP responses to exogenous Ang I were diminished in Ts, Gs, and Pg mice, whereas those to Ang II were the same in the different strains. Plasma and renal tissue Ang I of all transgenic mouse strains was significantly higher than WT, whereas Ang II levels were generally lower; aldosterone levels were significantly lower than WT in Ts mice but not in the two other transgenic strains. Our results demonstrate that vascular expression of sACE can largely but not completely restore TGF regulation of GFR. Proximal fluid reabsorption in the chronic absence of proximal tubule ACE is normal.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673