Examination of inhibition effect by monosaccharide analog for renal cyst progression in polycystic kidney disease

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08257
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Fujita Health University
• Principal Investigator: Nakajima Kazuki 藤田医科大学, 共同利用研究設備サポートセンター, 講師 (10442998)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 嚢胞性腎疾患群 / 糖脂質 / グルコース代謝 / 糖ヌクレオチド / グライコミクス / メタボロミクス / 細胞増殖

Outline of Final Research Achievements

Polycystic kidney disease is characterized by the progressive development of kidney and liver cysts. In this study, I elucidated how treatment with a modified sugar analog disrupts a biological pathway, which in turn block cyst progression.
6-alkynyl fucose was thought to block liver cyst progression via glycan changes, in contrast, 6-azido xylose blocked cell progression in renal cyst-derived cell lines. As other targets, 2-deoxyglucose and Venglustat, inhibitors of glucose metabolism and glycosphingolipid synthesis, cooperatively blocked the cell progression in the cyst-derived cells. Moreover, I identified novel monosaccharide-activated nucleotide sugars (GDP-2-deoxy-mannose and UDP-mannose) as key regulators in glycosylation. Therefore, our hypothesis will provide novel therapeutic targets and valuable insights regarding the molecular mechanisms in polycystic kidney diseases.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

嚢胞性腎疾患群に対する薬物治療法は、唯一トルバプタンのみであり新たな治療方法の確立が望まれている。今回の研究で検討した単糖代謝阻害剤は、その阻害剤の効果を高めることで新たなシード化合物になりえる。また、その阻害剤と別経路の糖脂質代謝阻害剤さらにトルバプタンの併用は、実臨床に近い薬剤を組み合わせた新たな併用療法につながると考えている。さらに今回の研究で検出された希少糖ヌクレオチドは、糖鎖修飾の新たな制御因子になりうることから、嚢胞腎研究や生化学研究において新たな発展が期待される。