Abstract
(Pro)renin receptor (PRR) has a single transmembrane domain that co-purifies with the vacuolar H+-ATPase (V-ATPase). In addition to its role in cellular acidification, V-ATPase has been implicated in membrane fusion and exocytosis via its Vo domain. Results from the present study show that PRR is expressed in pituitary adenoma cells and regulates growth hormone (GH) release via V-ATPase-induced cellular acidification. Positive PRR immunoreactivity was detected more often in surgically resected, growth hormone-producing adenomas (GHomas) than in nonfunctional pituitary adenomas. GHomas strongly expressing PRR showed excess GH secretion, as evidenced by distinctly high plasma GH and insulin-like growth factor-1 levels, as well as an elevated nadir GH in response to the oral glucose tolerance test. Suppression of PRR expression in rat GHoma-derived GH3 cells using PRR siRNA resulted in reduced GH secretion and significantly enhanced intracellular GH accumulation. GH3 treatment with bafilomycin A1, a V-ATPase inhibitor, also blocked GH release, indicating mediation via impaired cellular acidification of V-ATPase. PRR knockdown decreased Atp6l, a subunit of the Vo domain that destabilizes V-ATPase assembly, increased intracellular GH, and decreased GH release. To our knowledge, this is the first report demonstrating a pivotal role for PRR in a pituitary hormone release mechanism.
Highlights
Is abundantly present in the human anterior lobe[26]
Resected growth hormone-producing adenomas (GHomas) highly expressed PRR compared with the remaining human pituitary adenomas
Circulating growth hormone (GH)/IGF-1 levels in our acromegalic patients were remarkably increased as PRR expression in GHomas intensified, the levels were not associated with immunoreactive prorenin, suggesting a pivotal role for PRR in GH secretion, but not for prorenin
Summary
All RAS components coexist within the secretory granules of all cell types of the rat anterior pituitary[27], as well as lactotropes in normal human pituitary and PRL-secreting adenomas[28,29]. In the human hypothalamus and pituitary, PRR protein is localized to the paraventricular and supraoptic nuclei, as well as in anterior pituitary cells[26]. In GHomas, gain-of-function point mutations of the Gs protein, termed gsp, lead to constitutive adenylyl cyclase induction and are thought to promote GH secretion via GH-releasing hormone[30,31]. Gain-of-function point mutations account for 30–40% of GHomas[32,33,34]. The pathogenic mechanisms underlying excessive GH production in the remaining GHomas are unknown. Hormonal release mechanisms in pituitary tumors remain poorly understood
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