Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism

Ryusei Sugimoto, Hiroshi Watanabe, Komei Ikegami, Yuki Enoki, Tadashi Imafuku, Yoshiaki Sakaguchi, Michiya Murata, Kento Nishida, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)658-670
Number of pages13
JournalKidney international
Volume91
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1

Keywords

  • ABCG2
  • chronic kidney disease
  • parathyroid hormone
  • secondary hyperparathyroidism
  • urate

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism'. Together they form a unique fingerprint.

  • Cite this

    Sugimoto, R., Watanabe, H., Ikegami, K., Enoki, Y., Imafuku, T., Sakaguchi, Y., Murata, M., Nishida, K., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M., & Maruyama, T. (2017). Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism. Kidney international, 91(3), 658-670. https://doi.org/10.1016/j.kint.2016.09.041