1. The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals
- Author
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Yusuke Moritoh, Ryokichi Koyama, Akihiro Kobayashi, Masanori Watanabe, Shin-ichi Abe, Hiroki Akiyama, Ryoma Hara, and Shizuo Kasai
- Subjects
Virus genetics ,Inositol Phosphates ,Science ,General Physics and Astronomy ,Medicinal chemistry ,Phosphorus metabolism disorder ,Pyrophosphate ,Article ,General Biochemistry, Genetics and Molecular Biology ,Phosphates ,Receptors, G-Protein-Coupled ,chemistry.chemical_compound ,Adenosine Triphosphate ,Homeostasis ,Animals ,Humans ,Inositol ,Enzyme Inhibitors ,Renal Insufficiency, Chronic ,Phosphorus metabolism disorders ,Mammals ,chemistry.chemical_classification ,Phosphotransferases (Phosphate Group Acceptor) ,Multidisciplinary ,Kinase ,Biological Transport ,General Chemistry ,Phosphate ,Rats ,Hyperphosphatemia ,Enzyme ,chemistry ,Biochemistry ,Receptors, Virus ,Xenotropic and Polytropic Retrovirus Receptor ,Intracellular - Abstract
Circulating phosphate levels are tightly controlled within a narrow range in mammals. By using a novel small-molecule inhibitor, we show that the enzymatic activity of inositol hexakisphosphate kinases (IP6K) is essential for phosphate regulation in vivo. IP6K inhibition suppressed XPR1, a phosphate exporter, thereby decreasing cellular phosphate export, which resulted in increased intracellular ATP levels. The in vivo inhibition of IP6K decreased plasma phosphate levels without inhibiting gut intake or kidney reuptake of phosphate, demonstrating a pivotal role of IP6K-regulated cellular phosphate export on circulating phosphate levels. IP6K inhibition-induced decrease in intracellular inositol pyrophosphate, an enzymatic product of IP6K, was correlated with phosphate changes. Chronic IP6K inhibition alleviated hyperphosphataemia, increased kidney ATP, and improved kidney functions in chronic kidney disease rats. Our results demonstrate that the enzymatic activity of IP6K regulates circulating phosphate and intracellular ATP and suggest that IP6K inhibition is a potential novel treatment strategy against hyperphosphataemia., Inositol hexakisphosphate kinase (IP6K) is involved in diverse cellular signalling pathways, but the physiological roles of IP6K in vivo remain unknown in mammals. Here, the authors show that the enzymatic activity of IP6K is essential for phosphate regulation in vivo.
- Published
- 2021