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 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 deter- mined 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. J Am Soc Nephrol 16: 3535–3542, 2005. doi: 10.1681/ASN.2005020151 C ontrol of fluid homeostasis by the kidneys requires the participation of numerous paracrine agents that act in concert to regulate the formation of a large glomerular ultrafiltrate and the subsequent retrieval of essential constitu- ents along the tubular system. It has been recognized that among these regulatory pathways the renin-angiotensin-aldo- sterone system (RAAS) seems to play an important and per- haps dominant role (1). Both angiotensin II (Ang II) as the end product of the enzymatic actions of renin and angiotensin- converting enzyme (ACE) and aldosterone, which is secreted in response to Ang II, have profound effects on the absorption of NaCl and water in most segments of the renal nephron. In addition, Ang II is a vasoactive agent that affects GFR by vasoconstrictor actions in glomerular arterioles (2). Tubular absorption and glomerular filtration are linked by the tubulo- glomerular feedback (TGF) mechanism. As NaCl concentration rises in the tubular fluid passing the macula densa, for example as a result of a reduction in proximal fluid absorption, vaso- constriction of afferent arterioles occurs, and the resultant change of GFR limits the delivery of fluid to the late nephron (3). It is thought that this tubulovascular cross-talk assists in the preservation of electrolyte balance by limiting sodium excre- tion. Whereas adenosine acting through A1 adenosine recep- tors seems to be the direct mediator of this response, a substan- tial body of evidence indicates that the formation of Ang II is necessary for adenosine to exert its actions (4). Studies of the effects of pharmacologic inhibitors of the RAAS have been used widely to assess its role in physiology and pathophysiology. This approach was complemented re- cently by the development of mutant mouse strains defective in the expression of renin, renin substrate, ACE, or angiotensin receptors (5–9). The operation of the RAAS as a single func- tional unit is supported by the findings that all of these strains have essentially identical abnormalities, including arterial hy- potension, renal cortical and papillary atrophy, and hyperpla- sia of the renal vasculature. Specifically, ACE null mice that are generated in our laboratory in the FVB background have iden- tical renal defects: Hypotension and male sterility (10). In ad- dition, Ace-/- mice are runty and have a life expectancy of only 6 to 8 mo as a result of the severe renal defects. Although the occurrence of these abnormalities is highly informative in itself, the severity of the RAAS null phenotype limits the use- fulness of these animals for physiologic studies. Received February 8, 2005. Accepted August 24, 2005. Published online ahead of print. Publication date available at www.jasn.org. Address correspondence to: Dr. Sean P. Kessler, Department of Molecular Ge- netics NE20, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: 216-444-0884; Fax: 216-444-0512; E-mail: kessles@ccf.org Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1612-3535