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Genetic mapping of a modifier locus affecting hypertension in soluble guanylate cyclase α1 deficient mice
BMC Pharmacology volume 11, Article number: P14 (2011)
We previously reported that male mice deficient in the α1 subunit of the NO receptor soluble guanylate cyclase (sGCα1-/- mice), an important nitric oxide (NO) receptor, are hypertensive . The phenotype depends on the genetic background: sGCα1-/- mice on a 129S6 (S6) background (sGCα1-/-S6) but not on a C57BL/6 (B6) background
(sGCα1-/-B6) develop hypertension . These findings suggest that hypertension associated with sGCα1-deficiency is modulated by genetic factors. We aimed to identify modifier genes underlying the hypertension in sGCα1-/-S6 mice.
Materials and methods
Mean arterial blood pressure (MAP) was measured invasively in 280 male F2 offspring from a sGCα1-/-S6 X sGCα1-/-B6 intercross (sGCα1-/-F2). All mice were genotyped with a genome-wide panel of 150 SNP markers for linkage analysis using the Sequenom MassArray system and MAPMAKER/QTL. Renin-1c and renin-2d genotyping was performed using gene-specific primers. Plasma renin activity (PRA) and aldosterone were measured in anesthetized male S6 wild-type (WTS6) and sGCα1-/-S6 mice by radioimmunoassay and enzyme-linked immunoassay, respectively. The renin angiotensin system (RAS) was blocked by treating mice with either the aldosterone receptor antagonist, Spironolactone (100 mg/kg/day, subcutaneous pellet for 7 days), or the renin inhibitor, Aliskiren (200mg/kg/day, by gavage for 10 days).
MAP in sGCα1-/-F2 mice varied between values observed in sGCα1-/-S6 and sGCα1-/-B6 mice. Linkage analysis identified a locus on chromosome 1 with a highly significant logarithm of odds (LOD) score of 6.1. This region is syntenic with previously identified hypertension-related QTLs in the human and rat genome and contains the gene coding for renin. Importantly, B6 mice have one renin gene (renin-1c), and S6 mice have two renin genes (renin-1d and renin-2). Presence of the renin-1d and renin-2 genes correlated significantly with elevated MAP in the F2 mice (P<0.0001). PRA was higher in sGCα1-/-S6 than in WTS6 mice (0.29±0.01 vs. 0.23±0.03 µg angiotensin 1/ml/hr, respectively, P<0.05). Similarly, plasma aldosterone levels were higher in sGCα1-/-S6 than in WTS6 mice (0.47±0.03 vs 0.34±0.03 ng/ml, respectively, P<0.05). Treatment with Spironolactone or Aliskiren normalized blood pressure in sGCα1-/-S6 (117±5 vs 146±2 mmHg, in Spironolactone and vehicle-treated mice, respectively, P<0.001, and 100±7 vs 148±4 mmHg, in Aliskiren and vehicle-treated mice, respectively, P<0.001).
Together, these data identify renin as a possible genetic modifier of blood pressure in a setting of deficient NO-cGMP signaling. Furthermore, these findings highlight the importance of sGC in the regulation of the renin-angiotensin system (RAS) and suggest that sGC may be a therapeutic target in RAS-dependent hypertension.
Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, Dewerchin M, Bloch KD, Janssens S, Brouckaert P: Gender-specific hypertension and responsiveness to nitric oxide in sGCα1 knockout mice. Cardiovasc Res. 2008, 79: 179-186. 10.1093/cvr/cvn068.
Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai M, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, Scherrer-Crosbie M, Ichinose F, Brouckaert P, Bloch KD: sGCα1β1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol. 2009, 297: H654-663. 10.1152/ajpcell.00059.2009.
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Buys, E.S., Raher, M.J., Kirby, A. et al. Genetic mapping of a modifier locus affecting hypertension in soluble guanylate cyclase α1 deficient mice. BMC Pharmacol 11 (Suppl 1), P14 (2011). https://doi.org/10.1186/1471-2210-11-S1-P14
- Plasma Renin Activity
- Mean Arterial Blood Pressure