Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type.
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.
Takahashi
Nobuyuki
N
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
Lopez
Maria Luisa S Sequeira
ML
Cowhig
John E
JE
Taylor
Melissa A
MA
Hatada
Tomoko
T
Riggs
Emily
E
Lee
Gene
G
Gomez
R Ariel
RA
Kim
Hyung-Suk
HS
Smithies
Oliver
O
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
D012333:RNA, Messenger; D012076:Renal Agents; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D012083:Renin; D003894:Deamino Arginine Vasopressin