title: Regulation of growth hormone secretion by (pro)renin receptor.
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.
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tani
authors.affiliation: Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoshita
authors.affiliation: Institute of Biomedical Research and Innovation Hospital, Hyogo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D005260:Female; D015870:Gene Expression; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000378:metabolism; D015398:Signal Transduction; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C092037:ZBTB16 protein, human