EOS789, pan‐phosphate transporter inhibitor, ameliorates the progression of kidney injury in anti‐GBM‐induced glomerulonephritis rats

Tsuboi, Yoshinori; Ichida, Yasuhiro; Murai, Atsuko; Maeda, Akira; Iida, Manami; Kato, Atsuhiko; Ohtomo, Shuichi; Horiba, Naoshi

doi:10.1002/prp2.973

Cited by 5 publications

(5 citation statements)

References 38 publications

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“…SLC34 transporters are also inhibited by EOS789 but at slightly higher concentrations. The properties of EOS789 indicate that it has therapeutic potential for hyperphosphatemia associated with chronic kidney disease ( Tsuboi et al, 2020 ; Hill Gallant et al, 2021 ; Doshi and Wish, 2022 ; Tsuboi et al, 2022 ). For a recent review of Na + -Pi cotransporter pharmacology, see Wagner, 2023 .…”

Section: Pi Influx: Mammalian Na + -Pi Cotransportersmentioning

confidence: 99%

Role of transporters in regulating mammalian intracellular inorganic phosphate

Jennings

2023

Front. Pharmacol.

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This review summarizes the current understanding of the role of plasma membrane transporters in regulating intracellular inorganic phosphate ([Pi]In) in mammals. Pi influx is mediated by SLC34 and SLC20 Na+-Pi cotransporters. In non-epithelial cells other than erythrocytes, Pi influx via SLC20 transporters PiT1 and/or PiT2 is balanced by efflux through XPR1 (xenotropic and polytropic retrovirus receptor 1). Two new pathways for mammalian Pi transport regulation have been described recently: 1) in the presence of adequate Pi, cells continuously internalize and degrade PiT1. Pi starvation causes recycling of PiT1 from early endosomes to the plasma membrane and thereby increases the capacity for Pi influx; and 2) binding of inositol pyrophosphate InsP8 to the SPX domain of XPR1 increases Pi efflux. InsP8 is degraded by a phosphatase that is strongly inhibited by Pi. Therefore, an increase in [Pi]In decreases InsP8 degradation, increases InsP8 binding to SPX, and increases Pi efflux, completing a feedback loop for [Pi]In homeostasis. Published data on [Pi]In by magnetic resonance spectroscopy indicate that the steady state [Pi]In of skeletal muscle, heart, and brain is normally in the range of 1–5 mM, but it is not yet known whether PiT1 recycling or XPR1 activation by InsP8 contributes to Pi homeostasis in these organs. Data on [Pi]In in cultured cells are variable and suggest that some cells can regulate [Pi] better than others, following a change in [Pi]Ex. More measurements of [Pi]In, influx, and efflux are needed to determine how closely, and how rapidly, mammalian [Pi]In is regulated during either hyper- or hypophosphatemia.

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Section: Pi Influx: Mammalian Na + -Pi Cotransportersmentioning

confidence: 99%

Role of transporters in regulating mammalian intracellular inorganic phosphate

Jennings

2023

Front. Pharmacol.

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“…The target of hyperphosphatemia treatment is intestinal Pi absorption. Intestinal NaPi2b, PiT1, and PiT2 inhibitors have been developed [51][52][53]. EOS789, a pan-Pi transporter inhibitor, inhibits Pi absorption in the intestine through a distinct mechanism compared to Pi binders, with low absorption, minimal body accumulation, and potential for inhibiting Pi transport inhibition at low doses [38][39][40][41].…”

Section: Pi Transporters and Diseasementioning

confidence: 99%

Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism

Koike,

Uga,

Shiozaki

et al. 2023

Endocrines

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Phosphorus is essential for all living organisms. It plays an important role in maintaining biological functions, such as energy metabolism, cell membrane formation, and bone mineralization. Various factors in the intestine, kidneys, and bones regulate the homeostasis of the inorganic phosphate (Pi) concentration in the body. X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is characterized by an impaired mineralization of the bone matrix, hypertrophic chondrocytes with hypophosphatemia, and active vitamin D resistance in childhood. Phosphate-regulating gene with homologies to endopeptidases on the X chromosome was recognized as the responsible gene for XLH. XLH is classified as fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets. The enhanced FGF23 stimulates renal phosphate wasting by downregulating sodium-dependent Pi cotransporters, NaPi2a and NaPi2c proteins, in the proximal tubules. Recently, transmembrane protein (Tmem) 174 has been identified as a novel regulator of phosphate transporters. This review introduces the role of Tmem174 in the Pi homeostasis in the body.

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Section: Introductionmentioning

confidence: 99%

“…EOS789 is a pan-Pi transporter inhibitor with low absorption, low accumulation in the body, and potentially potent inhibition of Pi transport at low doses (2,(25)(26)(27). EOS789 interacts with several sodium-dependent phosphate transporters (NaPi-2b, Pit-1, and Pit-2) known to contribute to intestinal phosphate absorption (25)(26)(27). Furthermore, EOS789 was reported to improve hyperphosphatemia, severe glomerulosclerosis, tubular degeneration, and tubulointerstitial fibrosis and suppress vascular calcification in a rat model of CKD (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

“…EOS789 interacts with several sodium-dependent phosphate transporters (NaPi-2b, Pit-1, and Pit-2) known to contribute to intestinal phosphate absorption (25)(26)(27). Furthermore, EOS789 was reported to improve hyperphosphatemia, severe glomerulosclerosis, tubular degeneration, and tubulointerstitial fibrosis and suppress vascular calcification in a rat model of CKD (25)(26)(27). However, the effects of EOS789 on Pi metabolism compared to conventional Pi binders remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism : Comparison with a conventional phosphate binder

et al. 2023

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Background : Inorganic phosphate (Pi) binders are the only pharmacologic treatment approved for hyperphosphatemia. However, Pi binders induce the expression of intestinal Pi transporters and have limited effects on the inhibition of Pi transport. EOS789, a novel pan-Pi transporter inhibitor, reportedly has potent efficacy in treating hyperphosphatemia. We investigated the properties of EOS789 with comparison to a conventional Pi binder. Methods : Protein and mRNA expression levels of Pi transporters were measured in intestinal and kidney tissues from male Wistar rats fed diets supplemented with EOS789 or lanthanum carbonate (LC). 32 Pi permeability was measured in intestinal tissues from normal rats using a chamber. Results : Increased protein levels of NaPi-2b, an intestinal Pi transporter, and luminal Pi removal were observed in rats treated with LC but not in rats treated with EOS789. EOS789 but not LC suppressed intestinal protein levels of the Pi transporter Pit-1 and sodium / hydrogen exchanger isoform 3. 32 Pi flux experiments using small intestine tissues from rats demonstrated that EOS789 may affect transcellular Pi transport in addition to paracellular Pi transport. Conclusion : EOS789 has differing regulatory effects on Pi metabolism compared to LC. The properties of EOS789 may compensate for the limitations of LC therapy. The combined or selective use of EOS789 and conventional Pi binders may allow tighter control of hyperphosphatemia.

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EOS789, pan‐phosphate transporter inhibitor, ameliorates the progression of kidney injury in anti‐GBM‐induced glomerulonephritis rats

Cited by 5 publications

References 38 publications

Role of transporters in regulating mammalian intracellular inorganic phosphate

Role of transporters in regulating mammalian intracellular inorganic phosphate

Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism

Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism : Comparison with a conventional phosphate binder

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