The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals

Yusuke Moritoh (), Shin-ichi Abe, Hiroki Akiyama, Akihiro Kobayashi, Ryokichi Koyama, Ryoma Hara, Shizuo Kasai and Masanori Watanabe
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Yusuke Moritoh: SCOHIA PHARMA Inc
Shin-ichi Abe: SCOHIA PHARMA Inc
Hiroki Akiyama: SCOHIA PHARMA Inc
Akihiro Kobayashi: SCOHIA PHARMA Inc
Ryokichi Koyama: SCOHIA PHARMA Inc
Ryoma Hara: SCOHIA PHARMA Inc
Shizuo Kasai: SCOHIA PHARMA Inc
Masanori Watanabe: SCOHIA PHARMA Inc

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24934-8

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DOI: 10.1038/s41467-021-24934-8

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