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

Yusuke Moritoh,Ryokichi Koyama,Akihiro Kobayashi,Hiroki Akiyama,Masanori Watanabe,Ryoma Hara,Shin-Ichi Abe,Shizuo Kasai

doi:10.1038/s41467-021-24934-8

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.

Highlights

Circulating phosphate levels are tightly controlled within a narrow range in mammals
To determine whether phosphate uptake or export is controlled by pharmacological inhibition of IP6K, we evaluated the role of XPR1, a phosphate exporter, in the effects induced by IP6K inhibition in cells
This study illustrates the physiological significance of phosphate regulation by IP6K in vivo and provides a novel strategy to treat hyperphosphataemia and the associated complications using IP6K inhibitor-mediated suppression of cellular phosphate export (Fig. 7)

Summary

Introduction

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. 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 kinases (IP6K1, 2, and 3 in mammals) participate in diverse cellular signalling pathways by generating inositol pyrophosphates from their precursors[1,2]. The levels of inositol pyrophosphates are correlated with phosphate availability in yeast, fungi, plants, and animals[8,9]

Objectives

Methods

Conclusion