Molecular mechanism underlying secondary hyperparathyroidism in chronic kidney disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08561
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Yokohama City University
• Principal Investigator: Kataoka Kohsuke 横浜市立大学, 生命医科学研究科, 准教授 (20262074)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 副甲状腺 / 転写調節 / カルシウム恒常性

Outline of Final Research Achievements

Molecular mechanism of secondary hyperparathyroidism (SHPT) associated with chronic kidney disease is not fully understood. We have previously established a reporter assay system to monitor PTH gene enhancer activity by co-expression of parathyroid-enriched transcription factors, Gata3, Gcm2 and MafB into a non-parathyroid cell line. By using this system, we co-expressed receptors for extracellular calcium (CaSR), vitamin D (VDR and RXR) or FGF23 (FGFR1 and Klotho) and recaptured downregulation of PTH expression by these signaling molecules. These physiological responses are known to be compromised under SHPT condition through yet unidentified mechanisms. We therefore explored mechanism of the disability of repression by extracellular calcium, vitamin D and FGF23 through analyzing the synergistic transcriptional activities, post-translational modifications and protein stability of Gata3, Gcm2 and MafB.

Free Research Field

遺伝子発現調節

Academic Significance and Societal Importance of the Research Achievements

慢性腎不全における二次性副甲状腺機能亢進症SHPTは、QOLを大きく損なう要因のひとつであり、またリン・カルシウム代謝の破綻による血管内石灰化などを引き起こすことで生死に関わる問題を引き起こす。本来の生理的な状況下では、副甲状腺の機能は細胞外カルシウム、ビタミンD、FGF23によって抑制されるが、SHPTにおいては抑制機構が破綻するとされる。しかし、その抑制機構も、破綻の様相もあきらかではない。本研究は、副甲状腺機能と直結する副甲状腺ホルモンPTH遺伝子の発現調節に重要なエンハンサー活性を指標にして、転写調節の観点から生理的抑制機構とその破綻の分子機構の解明にアプローチした。