Identification of renin signaling as a blood pressure modifying mechanism in soluble guanylate cyclase α1-deficient mice

Abstract

Male mice deficient in the α 1 subunit of soluble guanylate cyclase, a nitric oxide (NO) receptor, are hypertensive when on a 129S6 (S6) background (sGC α 1 - / - S 6 ) but not when on a C57BL/6 (B6) background (sGC α 1 - / - B 6 ) , suggesting that hypertension associated with sGCα 1 -deficiency is modulated by genetic factors. Genetic linkage analyses in 284 male F2 offspring from an sGC α 1 - / - S 6 X sGC α 1 - / - B 6 intercross (sGC α 1 - / - F 2 ) revealed a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) with a maximal logarithm of the odds (LOD) score of 6.3. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS): plasma angiotensin II levels were higher in S6 mice than in B6 mice (of either genotype), and plasma aldosterone levels were greater in sGC α 1 - / - S 6 than in WT S6 mice. Renal function, as assessed by glomerular filtration rate, urinary volume and blood urea nitrogen, was similar in sGC α 1 - / - S 6 mice and in WT S6 mice. Inhibiting the RAAS normalized MAP and improved endothelium-dependent vasorelaxation in sGC α 1 - / - S 6 mice. These data identify the RAAS as a blood pressure-modifying signaling pathway in a setting of impaired NO-cGMP signaling. The finding that NO-cGMP and RAAS signaling (established pathways in the regulation of blood pressure) interact to regulate blood pressure, has great potential to advance our understanding of the etiology of human hypertension, and may help define genetically distinct subgroups of men and women with essential hypertension.