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Npr2 (natriuretic peptide receptor 2) affects bifurcation of neural crest or placode-derived afferents upon entering the brain stem/spinal cord, leading to a lack of either rostral or caudal branches. Previous work has shown that early embryonic growth of cochlear and vestibular afferents is equally affected in this mutant but later work on postnatal Npr2 point mutations suggested some additional effects on the topology of afferent projections and mild functional defects. Using multicolor lipophilic dye tracing, we show that absence of Npr2 has little to no effect on the initial patterning of inner ear afferents with respect to their dorsoventral cochleotopic-specific projections. However, in contrast to control animals, we found a variable degree of embryonic extension of auditory afferents beyond the boundaries of the anterior cochlear nucleus into the cerebellum that emanates only from apical spiral ganglion neurons. Such expansion has previously only been reported for Hox gene mutants and implies an unclear interaction of Hox codes with Npr2-mediated afferent projection patterning to define boundaries. Some vestibular ganglion neurons expand their projections to reach the cochlear apex and the cochlear nuclei, comparable to previous findings in Neurod1 mutant mice. Before birth, such expansions are reduced or lost leading to truncated projections to the anteroventral cochlear nucleus and expansion of low-frequency fibers of the apex to the posteroventral cochlear nucleus.

In 1981, de Bold and his colleagues made the seminal observation that infusion of extracts of atrial tissue into rats caused a copious natriuresis. 1 This then led to the isolation and cloning of atrial natriuretic peptide, the first member of a family of peptides with potent natriuretic, diuretic, and vasorelaxant activity. 2 Subsequent contributions from many investigators have expanded our understanding of the family of natriuretic peptides, their receptors, and their cellular actions that regulate physiologic functions. Studies using drugs to inhibit the function of some natriuretic peptide receptors or to prevent the degradation of natriuretic peptides have confirmed the importance . . .

Guanylyl cyclase B is the receptor for a small peptide (C-type natriuretic peptide) produced locally in many different tissues. To unravel the functions of the receptor, we generated mice lacking guanylyl cyclase B through gene targeting. Expression of the receptor mRNA in tissues such as bone and female reproductive organs was evident, and significant phenotypes associated with each of these tissues were apparent in null mice. A dramatic impairment of endochondral ossification and an attenuation of longitudinal vertebra or limb-bone growth were seen in null animals. C-type natriuretic peptide-dependent increases of guanylyl cyclase B activity, but not basal enzyme activity, appeared to be required for the progression of endochondral ossification. Female mice were infertile, but male mice were not. This result was due to the failure of the female reproductive tract to develop. Thus, the guanylyl cyclase B receptor is critical for the development of both bone and female reproductive organs.

Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p  = 0.009 and adult: +68 %, p  = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p  = 0.002 and adult: +134 %, p  = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45 + cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration.

Intractable gastrointestinal (GI) diseases often develop during infancy. Our group previously reported that natriuretic peptide receptor B (NPR-B)-deficient Npr2 slw/slw mice exhibit severe intestinal dysfunction, such as stenosis and distention, which resembles the dysfunction observed in Hirschsprung’s disease-allied disorders. However, the root cause of intestinal dysfunction and the detailed of pathophysiological condition in the intestine are not yet clear. Here, we report that the intestine of preweaning Npr2 slw/slw  mice showed bloodless blood vessels, and nodes were found in the lymphatic vessel. Additionally, the lacteals, smooth muscle, blood vessel, and nerves were barely observed in the villi of preweaning Npr2 slw/slw mice. Moreover, intramuscular interstitial cells of Cajal (ICC-IM) were clearly reduced. In contrast, villi and ICC-IM were developed normally in surviving adult Npr2 slw/slw mice. However, adult  Npr2 slw/slw mice exhibited partially hypoplastic blood vessels and an atrophied enteric nervous. Furthermore, adult Npr2 slw/slw mice showed markedly reduced white adipose tissue. These findings suggest that the cause of GI dysfunction in preweaning Npr2 slw/slw mice is attributed to defective intestinal development with microcirculation disorder. Thus, it is suggested that NPR-B signaling is involved in intestinal development and control of microcirculation and fat metabolism. This report provides new insights into intractable GI diseases, obesity, and NPR-B signaling.

Guanylyl cyclase-A (NPR-A; GC-A) is the major and possibly the only receptor for atrial natriuretic peptide (ANP) or B-type natriuretic peptide. Although mice deficient in GC-A display an elevated blood pressure, the resultant cardiac hypertrophy is much greater than in other mouse models of hypertension. Here we overproduce GC-A in the cardiac myocytes of wild-type or GC-A null animals. Introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype. Cardiac myocyte size was larger (approximately 20%) in GC-A null than in wild-type animals. However, introduction of the GC-A transgene reduced cardiac myocyte size in both wild-type and null mice. Coincident with the reduction in myocyte size, both ANP mRNA and ANP content were significantly reduced by overexpression of GC-A, and this reduction was independent of genotype. This genetic model, therefore, separates a regulation of cardiac myocyte size by blood pressure from local regulation by a GC-mediated pathway.

Earlier studies have shown the implication of growth factor receptor activation in angiotensin II (Ang II)-induced hyperproliferation of aortic VSMC as well as in hyperproliferation of VSMC from spontaneously hypertensive rats (SHR). We previously showed that NPR-C specific agonist C-ANP4-23 attenuates the hyperproliferation of VSMC from SHR through the inhibition of MAP kinase, Giα protein signaling and overexpression of cell cycle proteins. The aim of the present study was to investigate if C-ANP4-23- mediated attenuation of hyperproliferation of VSMC from SHR also involves growth factor receptor activation and upstream signaling molecules. For this study, C-ANP 4-23 (10 nmole/kg body weight) was injected intraperitoneally into 2 week-old prehypertensive SHR and Wistar Kyoto (WKY) rats twice per week for 6 weeks. The blood pressure in SHR was significantly attenuated by C-ANP4-23 treatment. In addition, C-ANP4-23 treatment also attenuated the hyperproliferation of VSMC from SHR as well as the enhanced phosphorylation of EGF-R, PDGF-R, IGF-R and c-Src. Furthermore, the enhanced levels of superoxide anion, NADPH oxidase activity, and enhanced expression of Nox4,Nox1,Nox2 and P47phox in SHR compared to WKY rats was also significantly attenuated by C-ANP4-23 treatment. In addition, N-acetyl cysteine (NAC), a scavenger of O2-, inhibitors of growth factor receptors and of c-Src, all inhibited the overexpression of cell cycle proteins cyclin D1 and cdk4 in VSMC from SHR. These results suggest that in vivo treatment of SHR with C-ANP4-23 inhibits the enhanced oxidative stress, c-Src and EGF-R, PDGF-R, IGF-R activation which through the inhibition of overexpression of cell cycle proteins result in the attenuation of hyperproliferation of VSMC.

Cerebral atrial natriuretic peptide (ANP), which is generated in the brain, has functions in the regulation of brain water and electrolyte balance, blood pressure and local cerebral blood flow, as well as in neuroendocrine functions. However, cerebral ANP clearance is still poorly understood. The purpose of this study was to clarify the mechanism of blood–brain (BBB) efflux transport of ANP in mouse. Western blot analysis showed expression of natriuretic peptide receptor (Npr)-A and Npr-C in mouse brain capillaries. The brain efflux index (BEI) method confirmed elimination of [125I]human ANP (hANP) from mouse brain across the BBB. Inhibition studies suggested the involvement of Npr-C in vivo. Furthermore, rapid internalization of [125I]hANP by TM-BBB4 cells (an in vitro BBB model) was significantly inhibited by Npr-C inhibitors and by two different Npr-C-targeted short interfering RNAs (siRNAs). Finally, treatment with 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) significantly increased Npr-C expression in TM-BBB4 cells, as determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted absolute proteomics. Our results indicate that Npr-C mediates brain-to-blood efflux transport of ANP at the mouse BBB as a pathway of cerebral ANP clearance. It seems likely that levels of natriuretic peptides in the brain are modulated by 1,25(OH)2D3 through upregulation of Npr-C expression at the BBB.

Sensory axon T-like branching (bifurcation) in neurons from dorsal root ganglia and cranial sensory ganglia depends on the molecular signaling cascade involving the secreted factor C-type natriuretic peptide, the natriuretic peptide receptor guanylyl cyclase B (GC-B; also known as Npr2) and cGMP-dependent protein kinase I (cGKI, also known as PKGI). The bifurcation of cranial nerves is suggested to be important for information processing by second-order neurons in the hindbrain or spinal cord. Indeed, mice with a spontaneous GC-B loss of function mutation ( ) display an impaired bifurcation of auditory nerve (AN) fibers. However, these mice did not show any obvious sign of impaired basal hearing. Here, we demonstrate that mice with a targeted inactivation of the GC-B gene (Npr2 , GC-B KO mice) show an elevation of audiometric thresholds. In the inner ear, the cochlear hair cells in GC-B KO mice were nevertheless similar to those from wild type mice, justified by the typical expression of functionally relevant marker proteins. However, efferent cholinergic feedback to inner and outer hair cells was reduced in GC-B KO mice, linked to very likely reduced rapid efferent feedback. Sound-evoked AN responses of GC-B KO mice were elevated, a feature that is known to occur when the efferent axo-dendritic feedback on AN is compromised. Furthermore, late sound-evoked brainstem responses were significantly delayed in GC-B KO mice. This delay in sound response was accompanied by a weaker sensitivity of the auditory steady state response to amplitude-modulated sound stimuli. Finally, the acoustic startle response (ASR) - one of the fastest auditory responses - and the prepulse inhibition of the ASR indicated significant changes in temporal precision of auditory processing. These findings suggest that GC-B-controlled axon bifurcation of spiral ganglion neurons is important for proper activation of second-order neurons in the hindbrain and is a prerequisite for proper temporal auditory processing likely by establishing accurate efferent top-down control circuits. These data hypothesize that the bifurcation pattern of cranial nerves is important to shape spatial and temporal information processing for sensory feedback control.

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs.