Stiftung Tierärztliche Hochschule Hannover (TiHo)

Natriuretic peptide expression and function in GH3 somatolactotropes and feline somatotrope pituitary tumours

Patients harbouring mutations in genes encoding C-type natriuretic peptide (CNP; <i>NPPC</i>) or its receptor guanylyl cyclase B (GC-B, <i>NPR2</i>) 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 <i>NPPC</i> and <i>NPR2</i> 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 <i>Nppc</i> was significantly enhanced following treatment with either 100 nM TRH or 10 µM forskolin, yet only <i>Npr1</i> expression was sensitive to forskolin stimulation; the effects of forskolin and TRH on <i>Nppc</i> expression were PKA- and MAPK-dependent, respectively. CNP stimulation of GH3 somatolactotropes significantly inhibited <i>Esr1, Insr</i> and <i>Lepr</i> expression, but dramatically enhanced <i>cFos</i> expression at the same time point. Oestrogen treatment significantly enhanced expression of <i>Nppa, Nppc, Npr1,</i> and <i>Npr2</i> 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. <i>NPPC</i> expression was negatively correlated with pituitary tumour volume and <i>SSTR5</i> expression, but positively correlated with <i>D2R</i> and <i>GHR</i> 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.

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