How Inorganic phosphate exporter Xpr1 regulates phosphate toxicity in aging

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K17800
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: The University of Tokushima
• Principal Investigator: SHIOZAKI Yuji 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (70908748)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: リン代謝 / リン毒性 / 老化 / Xpr1 / リン酸排出

Outline of Final Research Achievements

We hypothesized that Xpr1, an inorganic phosphate exporter, can reduces high phosphate-induced toxicity via regulating of intracellular inorganic phosphate levels. In this study, we conducted following research, 1) whether Xpr1 regulates intracellular phosphate levels and 2) whether knockout of Xpr1 aggravate high phosphate-induced toxicity. We prepared Xpr1 knockout (KO) proximal tubular cells by CRISPR-Cas9. Expression of phosphate transporter (Inward) such as NaPi2a and NaPi2c were downregulated in Xpr1 KO cells, but Xpr1 KO cells keep higher intracellular phosphate levels than WT cells after 3 hours incubation as efflux analysis. Xpr1 KO cells had high toxic sensitivity to high-phosphate media or Calciprotein particles (CPP) compared with WT cells. Accordingly, this research suggested that Xpr1 can regulate intracellular phosphate levels and inhibit phosphate-induced toxicity.

Free Research Field

分子栄養学

Academic Significance and Societal Importance of the Research Achievements

本研究では細胞レベルでのリン酸排出活性が高リンに対する毒性軽減に寄与することを示した。一方で、近位尿細管細胞ではXpr1抑制がリン酸排出だけでなくリン酸取り込みにも影響したことから、Xpr1活性は腎臓の再吸収などにも関与し血中リン濃度に影響する可能性があることが示唆される。今後、老化に伴って臓器・細胞のXpr1発現変化とリン毒性抑制への役割を明らかにすることで、Xpr1活性を標的とした創薬や食品成分によるリン毒性およびリン代謝制御を可能とし、リン関連疾患の治療・緩和につながることが期待される。