Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

Wang, Xiaojun; Xu, Yanping; Yu, Xin; Dey, Asim; Zhang, Hong Y.; Zink, Charity; Wodka, Derek; Porter, Gina; Matter, William F.; Porras, Leah L.; Reidy, Charles; Peterson, Jeffery A.; Mattioni, Brian E.; Haas, Joseph V.; Kowala, Mark C.; Wetterau, John R.

doi:10.1002/prp2.938

Cited by 3 publications

(12 citation statements)

References 53 publications

(148 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been found that 40 mg/kg of AlP is a fatal dose of this toxicant (about 4-fold of the aluminum phosphide LD50) [ [22] , [23] , [24] , [25] ]. A wide range of SVLM doses (from low doses to 1500 mg/kg) has been investigated in animal models [ 26 , 27 ]. In the current study, we used a minimum low dose of this drug to emphasize the potency of SVLM against AlP poisoning.…”

Section: Methodsmentioning

confidence: 99%

Repurposing of sevelamer as a novel antidote against aluminum phosphide poisoning: An in vivo evaluation

Heidari¹,

Mohammadi²,

Goudarzi³

et al. 2023

Heliyon

View full text Add to dashboard Cite

Section: Methodsmentioning

confidence: 99%

Repurposing of sevelamer as a novel antidote against aluminum phosphide poisoning: An in vivo evaluation

Heidari¹,

Mohammadi²,

Goudarzi³

et al. 2023

Heliyon

View full text Add to dashboard Cite

“…Generation of inducible human, mouse, and rat NPT2b overexpressing T-Rex™ Chinese Hamster Ovary (CHO, Thermo Fisher Scientific) cells and the NPT2b activity assay were described previously [21]. Briefly, cells were plated in 96-well CytoStar-T 1 scintillating microplates and were incubated overnight in medium plus 100 ng/mL of tetracycline to induce the expression of human NPT2b.…”

Section: Npt2b Pit-2 and Sglt1 Activity Assaysmentioning

confidence: 99%

“…Generation of constitutive human Pit-2 and SGLT1 overexpressing CHO cells and activity assays measuring the uptake of 33 P phosphate for 45 minutes at 20˚C for Pit-2 and 14 C-αmethyl-D-glucopyranoside for 120 minutes at 37˚C for SGLT1, were also described previously [21].…”

Section: Plos Onementioning

confidence: 99%

“…An ideal therapy to decrease intestinal phosphate absorption would decrease both active and passive diffusional transports. To explore this, we previously tested the ability of a potent NPT2b inhibitor to work alone and in combination with the phosphate binder, sevelamer, in two preclinical animal models [21]. While NPT2b had a prominent role in the acute uptake of phosphate into plasma of mice, NPT2b inhibition minimally affected phosphate absorption over time, highlighting the ability of other phosphate absorption pathways to compensate for the loss of NPT2b activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models

Wang,

Yu,

Gavardinas

et al. 2024

PLoS ONE

Self Cite

View full text Add to dashboard Cite

Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

show abstract

“…Current clinical strategies for treating ESRD patients include dietary phosphate restriction, hemodialysis, and the use of phosphate binders to reduce the serum phosphate concentration [6][7][8]. However, poor patient compliance, a heavy economic burden, and gastrointestinal (GI) side effects lead to these treatments having limited effect [9][10][11]. Thus, novel therapeutic strategies are needed.…”

Section: Introductionmentioning

confidence: 99%

Effects of the novel sodium-dependent phosphate cotransporter 2b inhibitor DZ1462 on hyperphosphatemia in chronic kidney disease

2024

Am J Transl Res

View full text Add to dashboard Cite

Background: Serum phosphate levels remain insufficiently controlled in chronic kidney disease (CKD) patients, and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodiumdependent phosphate cotransporter type 2b (NPT2b) holds promise as one such strategy. Methods: The in vitro cellular potency of DZ1462 was evaluated using a radioactive Pi uptake assay on stable Chinese hamster ovary (CHO) cell clones transfected with human NPT2b (hNPT2b) or rat NPT2b (rNPT2b). The ability of DZ1462 to inhibit phosphate absorption was studied in vivo in an acute model after oral bolus challenge with 33 PO 4 and in an adenineinduced chronic hyperphosphatemia rat model. PK and minitox was also evaluated. Results: The cellular assays with the hNPT2b-CHO and rNPT2b-CHO clones showed that DZ1462 significantly and potently inhibited phosphate uptake. In vivo, in a chronic Pi-fed rat model, DZ1462 effectively inhibited intestinal Pi uptake. In a hyperphosphatemia rat model, DZ1462 significantly inhibited Pi uptake, and DZ1462 in combination with sevelamer had a synergistic effect. The pharmacokinetics (PK) study confirmed that DZ1462 is a gastrointestinal (GI)-restricted compound that can remain in the intestine for a sufficient duration. In addition, DZ1462 also reduced cardiovascular events and ameliorated osteoporosis in a CKD animal model. Conclusions: This study revealed that a GI-restricted NPT2b inhibitor DZ1462 potently inhibits NPT2b in vitro and blocks intestinal phosphate uptake in multiple animal models with potential to reduce various cardiovascular events in CKD models. Therefore, DZ1462 may be useful to treat renal disease patients who have shown an unsatisfactory response to phosphate binders.

show abstract

Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

Cited by 3 publications

References 53 publications

Repurposing of sevelamer as a novel antidote against aluminum phosphide poisoning: An in vivo evaluation

Repurposing of sevelamer as a novel antidote against aluminum phosphide poisoning: An in vivo evaluation

Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models

Effects of the novel sodium-dependent phosphate cotransporter 2b inhibitor DZ1462 on hyperphosphatemia in chronic kidney disease

Contact Info

Product

Resources

About