Genetic disruption of atrial natriuretic peptide receptor-A alters renin and angiotensin II levels.
We have studied cardiovascular and renal phenotypes in Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) gene-disrupted mutant mouse model. The baseline systolic arterial pressure (SAP) in 0-copy mutant (-/-) mice (143 +/- 2 mmHg) was significantly higher than in 2-copy wild-type (+/+) animals (104 +/- 2 mmHg); however, the SAP in 1-copy heterozygotes (+/-) was at an intermediate value (120 +/- 4 mmHg). To determine whether Npr1 gene function affects the renin-angiotensin-aldosterone system (RAAS), we measured the components of RAAS in plasma, kidney, and adrenal gland of 0-copy, 1-copy, and 2-copy male mice. Newborn (2 days after the birth) 0-copy pups showed 2.5-fold higher intrarenal renin contents compared with 2-copy wild-type counterparts (0-copy 72 +/- 12 vs. 2-copy 30 +/- 7 microg ANG I. mg protein(-1). h(-1), respectively). The intrarenal ANG II level in 0-copy pups was also higher than in 2-copy controls (0-copy 33 +/- 5 vs. 2-copy 20 +/- 2 pg/mg protein, respectively). However, both young (3 wk) and adult (16 wk) 0-copy mutant mice showed a dramatic 50-80% reduction in plasma renin concentrations (PRCs) and in expression of renal renin message compared with 2-copy control animals. In contrast, the adrenal renin content and mRNA expression levels were 1.5- to 2-fold higher in 0-copy adult mice than in 2-copy animals. The results suggest that inhibition of renal and systemic RAAS is a compensatory response that prevents greater increases in elevated arterial pressures in adult NPRA null mutant mice. However, the greater renin and ANG II levels seen in 0-copy newborn pups provide evidence that the direct effect of NPRA activation on renin is an inhibitory response.
Shi
S J
SJ
Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Nguyen
H T
HT
Sharma
G D
GD
Navar
L G
LG
Pandey
K N
KN
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D015870:Gene Expression / Q000502:physiology; D005838:Genotype; D006162:Guanylate Cyclase / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D000804:Angiotensin II; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D012083:Renin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A