Abstract
Patients harbouring mutations in genes encoding C-type natriuretic peptide (CNP; NPPC) or its receptor guanylyl cyclase B (GC-B, NPR2) suffer from severe growth phenotypes; loss-of-function mutations cause achondroplasia, whereas gain-of-function mutations cause skeletal overgrowth. Although most of the effects of CNP/GC-B on growth are mediated directly on bone, evidence suggests the natriuretic peptides may also affect anterior pituitary control of growth. Our previous studies described the expression of NPPC and NPR2 in a range of human pituitary tumours, normal human pituitary, and normal fetal human pituitary. However, the natriuretic peptide system in somatotropes has not been extensively explored. Here, we examine the expression and function of the CNP/GC-B system in rat GH3 somatolactotrope cell line and pituitary tumours from a cohort of feline hypersomatotropism (HST; acromegaly) patients. Using multiplex RT-qPCR, all three natriuretic peptides and their receptors were detected in GH3 cells. The expression of Nppc was significantly enhanced following treatment with either 100 nM TRH or 10 µM forskolin, yet only Npr1 expression was sensitive to forskolin stimulation; the effects of forskolin and TRH on Nppc expression were PKA- and MAPK-dependent, respectively. CNP stimulation of GH3 somatolactotropes significantly inhibited Esr1, Insr and Lepr expression, but dramatically enhanced cFos expression at the same time point. Oestrogen treatment significantly enhanced expression of Nppa, Nppc, Npr1, and Npr2 in GH3 somatolactotropes, but inhibited CNP-stimulated cGMP accumulation. Finally, transcripts for all three natriuretic peptides and receptors were expressed in feline pituitary tumours from patients with HST. NPPC expression was negatively correlated with pituitary tumour volume and SSTR5 expression, but positively correlated with D2R and GHR expression. Collectively, these data provide mechanisms that control expression and function of CNP in somatolactotrope cells, and identify putative transcriptional targets for CNP action in somatotropes.
Highlights
The natriuretic peptides (Arial, B-type, and C-type natriuretic peptides; ANP, BNP, CNP) have been characterised extensively in multiple species [1,2,3], where they have been shown to act as regulators of the cardiovascular system
We provide further evidence for a regulated natriuretic peptide system in pituitary tumour-derived GH3 cells as well as in feline patients with hypersomatotropism due to pituitary tumours
CNP performs a broader range of biological functions throughout the CNS and peripheral tissues compared with the predominantly cardiovascular roles for ANP and BNP, it is the effects of CNP on endocrine ossification that are best described
Summary
The natriuretic peptides (Arial, B-type, and C-type natriuretic peptides; ANP, BNP, CNP) have been characterised extensively in multiple species [1,2,3], where they have been shown to act as regulators of the cardiovascular system. Whilst ANP and BNP act predominantly to regulate cardiac function and natriuresis, it is clear that CNP exerts multiple effects throughout the body, acting as an autocrine/paracrine regulator in many endocrine tissues [2]. The majority of these effects are mediated via the receptor guanylyl cyclases (GC-A (for ANP and BNP), and GC-B (for CNP)), leading to the generation of cyclic guanosine 3 ,5 monophosphate (cGMP) and activation of protein kinase G (PKG) [3]. Our previous studies have shown the expression of a natriuretic peptide system in a range of human pituitary tumours, regardless of the cell type of origin [9]. We provide the first description of a natriuretic peptide system in feline pituitaries
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