Interactive roles of NPR1 gene-dosage and salt diets on cardiac angiotensin II, aldosterone and pro-inflammatory cytokines levels in mutant mice

Objective: The objective of the present study was to elucidate the interactive roles of guanylyl cyclase/natriuretic peptide receptor-A (NPRA) gene (Npr1) and salt diets on cardiac angiotensin II (ANG II), aldosterone and pro-inflammatory cytokines levels in Npr1 gene-targeted (1-copy, 2-copy, 3-copy, 4-copy) mice. Methods: Npr1 genotypes included 1-copy gene-disrupted heterozygous (+/-), 2-copy wild-type (+/+), 3-copy gene-duplicated heterozygous (++/+) and 4-copy gene-duplicated homozygous (++/++) mice. Animals were fed low, normal and high-salt diets. Plasma and cardiac levels of ANG II, aldosterone and pro-inflammatory cytokines were determined. Results: With a high-salt diet, cardiac ANG II levels were increased (+) in 1-copy mice (13.7 +/- 2.8 fmol/mg protein, 111%) compared with 2-copy mice (6.5 +/- 0.6), but decreased (-) in 4-copy (4.0 +/- 0.5, 38%) mice. Cardiac aldosterone levels were increased (+) in 1-copy mice (80 +/- 4 fmol/mg protein, 79%) compared with 2-copy mice (38 +/- 3). Plasma tumour necrosis factor alpha was increased (+) in 1-copy mice (30.27 +/- 2.32 pg/ml, 38%), compared with 2-copy mice (19.36 +/- 2.49, 24%), but decreased (-) in 3-copy (11.59 +/- 1.51, 12%) and 4-copy (7.13 +/- 0.52, 22%) mice. Plasma interleukin (IL)-6 and IL-1 alpha levels were also significantly increased (+) in 1-copy compared with 2-copy mice but decreased (-) in 3-copy and 4-copy mice. Conclusion: These results demonstrate that a high-salt diet aggravates cardiac ANG II, aldosterone and pro-inflammatory cytokine levels in Npr1 gene-disrupted 1-copy mice, whereas, in Npr1 gene-duplicated (3-copy and 4-copy) mice, high salt did not render such elevation, suggesting the potential roles of Npr1 against salt loading.