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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