Genetic mouse models with disruption of both Nppa (coding for proANP) and Npr1 (coding for GC-A/NPRA) have provided strong support for the central role of the natriuretic peptide hormone–receptor system in the regulation of arterial pressure [21,104–109]. Therefore, genetic defects that reduce the activity of ANP and its receptor system can be considered as candidate contributors to essential hypertension . Previous studies with ANP-deficient (Nppa−/−) mice demonstrated that a defect in proANP synthesis can cause hypertension . The blood pressure of homozygous null mutant mice was elevated by 8–23 mmHg when they were fed with standard-salt or intermediate-salt diets. Those previous findings indicated that genetic disruption of ANP production can lead to hypertension. Transgenic mice overexpressing ANP developed sustained hypotension with an arterial pressure that was 25–30 mmHg lower than that of their nontransgenic siblings [110,111]. Interestingly, somatic delivery of the ANP gene in spontaneously hypertensive rats induced a sustained reduction of systemic blood pressure . Overexpression of ANP in hypertensive mice lowered systolic blood pressure, raising the possibility of using ANP gene therapy for the treatment of human hypertension . It has also been shown that functional alterations of the Nppa promoter are linked to cardiac hypertrophy in progenies of crosses between Wistar Kyoto and Wistar Kyoto-derived hypertensive rats, and that a single-nucleotide polymorphism can alter the transcriptional activity of the proANP gene promoter .
Genetic studies with Npr1 knockout (Npr1−/− or zero-copy) mice have indicated that disruption of Npr1 increases blood pressure by 35–40 mmHg as compared with wild-type (Npr1+/+ or two-copy) animals [21,104,109]. It has been demonstrated that complete absence of NPRA causes hypertension in mice and leads to altered renin and angiotensin II levels [21,104,109,115–117]. In contrast, increased expression of NPRA in gene-duplicated mutant mice significantly reduces blood pressure and increases the levels of cGMP, in correspondence with the increasing number of Npr1 copies [106,115,116,118]. Our studies have examined the quantitative contributions and possible mechanisms mediating the responses of varying numbers of Npr1 copies by determining the renal plasma flow, glomerular filtration rate, urine flow and sodium excretion patterns following blood volume expansion in Npr1-targeted mice in a gene dose-dependent manner [105,116]. Our findings demonstrated that the ANP–NPRA axis is primarily responsible for mediating the renal hemodynamic and sodium excretory responses to intravascular blood volume expansion. Interestingly, the ANP–NPRA system inhibits aldosterone synthesis and release from adrenal glomerulosa cells [3,109,115,119], which may account for its renal natriuretic and diuretic effects. Furthermore, studies with Npr1-disrupted (zero-copy) mice demonstrated that, at birth, the absence of NPRA allows higher renin and angiotensin II levels than in wild-type mice, and increased renin mRNA expression . However, at 3–16 weeks of age, the circulating renin and angiotensin II levels were dramatically decreased in Npr1 homozygous null mutant mice as compared with wild-type (two-copy) control mice. The decrease in renin activity in adult Npr1 null mutant mice is probably caused by a progressive elevation in arterial pressure, leading to inhibition of renin synthesis and release from the kidney juxtaglomerular cells . On the other hand, the adrenal renin content and renin mRNA level, as well as angiotensin II and aldosterone concentrations, were elevated in adult homozygous null mutant mice as compared with wild-type mice [109,115]. In light of these previous findings, it can be suggested that the ANP–NPRA signaling system may play a key regulatory role in the maintenance of both systemic and tissue levels of the components of the renin–angiotensin–aldosterone (RAA) system in physiological and pathological conditions. Indeed, ANP–NPRA signaling appears to oppose almost all actions of angiotensin II in both physiological and disease states (Table 2). Although expression of ANP and BNP is markedly increased in patients with hypertrophic or failing hearts, it is unclear how the natriuretic peptide system is activated to play a protective role. The ANP–NPRA system may act by reducing high blood pressure and inhibiting the RAA system, or by activating new molecular targets as a consequence of the hypertrophic changes occurring in the heart [21,105,120,121].