title: Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism.
abstract: Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Ryusei
authors.initials: R
authors.lastname: Sugimoto
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Komei
authors.initials: K
authors.lastname: Ikegami
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Enoki
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Imafuku
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sakaguchi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Michiya
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Miyamura
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Department of Nephrology, Akebono Clinic, Kumamoto, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Nephrology, Akebono Clinic, Kumamoto, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Komaba
authors.affiliation: Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan; DDS Research Institute, Sojo University, Kumamoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D057966:Calcimimetic Agents / Q000627:therapeutic use; D000069449:Cinacalcet / Q000627:therapeutic use; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D033461:Hyperuricemia / Q000097:blood / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D066237:Intestinal Elimination; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination; D013997:Time Factors; D014511:Uremia / Q000097:blood / Q000150:complications; D014527:Uric Acid / Q000097:blood*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C489249:Abcg2 protein, rat; D057966:Calcimimetic Agents; D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D014527:Uric Acid; D000069449:Cinacalcet
keywords: ABCG2; chronic kidney disease; parathyroid hormone; secondary hyperparathyroidism; urate