Expression of guanylyl cyclase-B (GC-B/NPR2) receptors in normal human fetal pituitaries and human pituitary adenomas implicates a role for C-type natriuretic peptide

Abstract

C-type natriuretic peptide (CNP/Nppc) is expressed at high levels in the anterior pituitary of rats and mice and activates guanylyl cyclase B receptors (GC-B/Npr2) to regulate hormone secretion. Mutations in NPR2/Npr2 can cause achondroplasia, GH deficiency, and female infertility, yet the normal expression profile within the anterior pituitary remains to be established in humans. The current study examined the expression profile and transcriptional regulation of NPR2 and GC-B protein in normal human fetal pituitaries, normal adult pituitaries, and human pituitary adenomas using RT-PCR and immunohistochemistry. Transcriptional regulation of human NPR2 promoter constructs was characterized in anterior pituitary cell lines of gonadotroph, somatolactotroph, and corticotroph origin. NPR2 was detected in all human fetal and adult pituitary samples regardless of age or sex, as well as in all adenoma samples examined regardless of tumor origin. GC-B immunoreactivity was variable in normal pituitary, gonadotrophinomas, and somatotrophinomas. Maximal transcriptional regulation of the NPR2 promoter mapped to a region within K214 bp upstream of the start site in all anterior pituitary cell lines examined. Electrophoretic mobility shift assays revealed that this region contains Sp1/Sp3 response elements. These data are the first to show NPR2 expression in normal human fetal and adult pituitaries and adenomatous pituitary tissue and suggest a role for these receptors in both pituitary development and oncogenesis, introducing a new target to manipulate these processes in pituitary adenomas.

The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth

“…CNP was first isolated from porcine brain23 and is distributed throughout the brain and pituitary682425. In the cardiovascular system, CNP is expressed in endothelial cells, where it acts as a vascular mediator regulating local vascular tone and growth9102627.…”

Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas

“…This later gene has been demonstrated that is expressed exclusively in the Rathke's pouch and adenohypophysis during the development of pituitary in both chicken and mouse embryos and not in the neuroectoderm (Proszkowiec-Weglarz et al 2011). By using these expressions it could be concluded that all pituitary samples used as normal contained all five adenohypophophysis specific cell types (data not shown) [15][16][17][18]. Tumor tissue specimens were immediately frozen in liquid nitrogen after the adenoma removal, and stored at -80 o C until use.…”

Gonadotropes and Gonadotropin-Releasing Hormone Signaling

“…They act via cell surface receptors with intrinsic guanylyl cyclase activity termed NPR1 (GC-A) and NPR2 (GC-B). [695][696][697][698][699][700][701] Thus, the anterior pituitary contains the highest tissue concentration of CNP, and immunostaining revealed particularly strong expression in gonadotropes, 702 where it is found within secretory vesicles. 667,695 NPR1 is selectively activated by ANP and BNP, whereas NPR2 is selective for CNP, and all mediate elevation of cGMP levels in their target cells.…”

“…ANP and BNP are well-characterized regulators of cardiac and renal function, but the physiological roles of CNP are less clear. 651,700,701 Although CNP does not stimulate LH secretion or modulate GnRH-stimulated LH secretion, 695,698,700 work with gonadotrope-derived cell lines reveals that it can stimulate the human αGSU promoter 700 and that GnRH may stimulate CNP expression (transcriptional regulation of the proximal Nppc gene). 342 Female mice with this deletion are also infertile, as are mice in which the gene encoding GC-B (Npr2) is deleted, and this is consistent with evidence supporting a role for CNP in the hypothalamo-pituitary-gonadal axis.…”