title: Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA. ntakaha@med.unc.edu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Maria Luisa S Sequeira
authors.initials: ML
authors.lastname: Lopez
authors.forename: John E
authors.initials: JE
authors.lastname: Cowhig
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Taylor
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hatada
authors.forename: Emily
authors.initials: E
authors.lastname: Riggs
authors.forename: Gene
authors.initials: G
authors.lastname: Lee
authors.forename: R Ariel
authors.initials: RA
authors.lastname: Gomez
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D007022:Hypotension / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011141:Polyuria / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000502:physiology; D012076:Renal Agents / Q000494:pharmacology; D012083:Renin / Q000097:blood / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D012076:Renal Agents; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D012083:Renin; D003894:Deamino Arginine Vasopressin