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Ren1c Homozygous Null Mice Are Hypotensive and Polyuric, but Heterozygotes Are Indistinguishable from Wild-Type

Nobuyuki Takahashi^*,, Maria Luisa S. Sequeira Lopez, John E. Cowhig, Jr.^*, Melissa A. Taylor^*, Tomoko Hatada^*, Emily Riggs^*, Gene Lee^*,, R. Ariel Gomez, Hyung-Suk Kim^* and Oliver Smithies^*

Departments of ^* Pathology and Laboratory Medicine and Cell and Molecular Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pediatrics, University of Virginia, Charlottesville, Virginia; and Department of Oral Biochemistry College of Dentistry, Seoul National University, Seoul, Korea

Address correspondence to: Dr. Nobuyuki Takahashi, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912; Fax: 919-966-8800; E-mail: ntakaha{at}med.unc.edu

Mice lacking Ren1c were generated using C57BL/6-derived embryonic stem cells. Mice homozygous for Ren1c disruption (Ren1c–/–) are born at the expected ratio, but approximately 80% die of dehydration within a few days. The surviving Ren1c–/– mice have no renin mRNA expression in the kidney, hydronephrosis, thickening of renal arterial walls, and fibrosis in the kidney. Plasma renin and angiotensins I and II are undetectable. Urinary aldosterone is 6% wild-type. They have low tail-cuff BP (84 ± 4 versus 116 ± 5 mmHg in +/+) and excrete large amounts of urine (5.2 ± 0.8 ml/d, 725 ± 34 mOsm versus 1.1 ± 0.1 ml/d, 2460 ± 170 mOsm in +/+). After 5 d of drinking 5% dextrose, desmopressin does not increase the osmolality of the urine in –/– mice (624 ± 19 to 656 ± 25 mOsm), whereas in +/+, it increases severalfold (583 ± 44 to 2630 ± 174 mOsm). Minipump infusion of angiotensin II to Ren1c–/– mice restores BP to wild-type level, but preexisting damage to the medulla prevents complete restoration of the ability of the kidney to concentrate urine. Heterozygous Ren1c+/– mice, in contrast, are indistinguishable from +/+ in BP, urine volume, and osmolality. Kidney renin mRNA, the number of kidney cells producing renin, and plasma renin concentration in the Ren1c+/– mice are also indistinguishable from +/+. These results demonstrate that renin is the only enzyme capable of maintaining plasma angiotensins and that renin expression in the kidney is very tightly regulated at the mRNA level.

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