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264 DISRUPTION OF NATRIURETIC PEPTIDE RECEPTOR A GENE INCREASES ADRENAL ANGIOTENSIN II AND ALDOSTERONE LEVELS.
  1. D. Zhao1,
  2. N. K. Somanna1,
  3. K. N. Pandey1
  1. 1Department of Physiology, Tulane University Health Sciences Center School of Medicine, New Orleans, LA

Abstract

The disruption of guanylyl cyclase/natriuretic peptide receptor A (GC-A/NPRA) gene (Npr1) leads to elevated arterial blood pressure, cardiac hypertrophy, congestive heart failure, and sudden death in mice lacking NPRA. ANP-NPRA signaling is known to counteract the renin-angiotensin-aldosterone system (RAAS). We studied whether Npr1 gene copy number affects adrenal angiotensin II (Ang II) and aldosterone (ALDO) levels in a gene-dose dependent manner in Npr1 gene-targeted mice. Adrenal Ang II and ALDO levels increased in one-copy (gene-disrupted heterozygous allele, 15%, p < .05, 38%, p < .05) mice compared with two-copy (wide type) mice but decreased in three-copy (gene-duplicated heterozygous allele, 17%, p < .05, 13%, p < .05) and four-copy (gene-duplicated homozygous allele, 33%, p < .01, 38%, p < .001) mice. Interestingly, renal Ang II levels decreased in one-copy (25%, p < .05), three-copy (38%, p < .01), and four-copy (39%, p < .01) mice compared with two-copy mice. A low-salt diet increased adrenal Ang II and ALDO levels in one-copy (20%, p < .05, 2,441%, p < .001), two-copy (15%, p < .05, 2,339%, p < .001), three-copy (20%, p < .05, 424%, p < .001), and four-copy (31%, p < .05, 486%, p < .001) mice. On the other hand, a high-salt diet decreased adrenal Ang II and ALDO levels in one-copy (46%, p < .001, 29%, p < .05) and two-copy (38%, p < .01, 17%, p < .05) mice. Low-salt diet increased renal Ang II levels in one-copy (45%, p < .05), two-copy (45%, p < .05), three-copy (59%, p < .05), and four-copy (48%, p < .05) mice, whereas a high-salt diet decreased renal Ang II levels in one-copy (28%, p < .05) and two-copy (27%, p < .05) mice. The results suggest that ANP-NPRA signaling antagonizes adrenal Ang II and ALDO levels in a gene-dose-dependent manner. Our findings indicate that increased adrenal Ang II and ALDO levels play an important role in elevated blood pressure in Npr1 gene-disrupted mice.

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