Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney

Fujii, Tomoyuki; Shiozaki, Yuji; Segawa, Hiroko; Nishiguchi, Shiori; Hanazaki, Ai; Noguchi, Miwa; Kirino, Ruri; Sasaki, Shiro; Tanifuji, Kazuya; Koike, Megumi; Yokoyama, Mizuki; Arima, Yuki; Kaneko, Ichiro; Tatsumi, Sawako; Ito, Mikiko; Miyamoto, Ken‐ichi

doi:10.1007/s10157-018-1653-4

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…So far, no specific Npt2a-I was available to determine this contribution. Of note, in addition to Npt2a, OK cells also express Npt2c, PiT1, and PiT2 (25,27). However, the exact contribution of each of these proteins for P i transport remains speculative.…”

Section: Discussionmentioning

confidence: 99%

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PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies

Thomas

Xue

Tomilin

et al. 2020

American Journal of Physiology-Renal Physiology

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Plasma phosphate (Pi) levels are tightly controlled, and elevated plasma Pi levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of Pi reabsorption, the Na+-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70-80% of Pi reabsorption. The aim of this study was to determine the in vitro effects of a novel Npt2a inhibitor (Npt2a-I, PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a-/-) mice. In OK cells, Npt2a-I caused dose-dependent reductions of Na+-dependent Pi uptake (IC50: ~1.4 μmol/L), while the unselective Npt2 inhibitor phosphonoformic acid (PFA) resulted in a ~20% stronger inhibition of Pi uptake. The dose-dependent inhibitory effects were present after 24-hour incubation with both low and high Pi media. Michaelis-Menten kinetics in OK cells identified a ~2.4-fold higher Km for Pi in response to Npt2a inhibition with no significant change in apparent Vmax. Higher PTH concentrations decreased Pi uptake equivalent to the maximal inhibitory effect of Npt2a-I. In vivo, the Npt2a-I induced a dose-dependent increase in urinary Pi excretion in wild-type mice (ED50: ~23 mg/kg), which was completely absent in Npt2a-/- mice, alongside a lack of decrease in plasma Pi. Of note, the Npt2a-I-induced dose-dependent increase in urinary Na+ excretion was still present in Npt2a-/- mice, a response possibly mediated by an off-target acute inhibitory effect of the Npt2a-I on open probability of the epithelial Na+ channel, ENaC, in the cortical collecting duct.

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Section: Discussionmentioning

confidence: 99%

“…In particular, OK cells have been extensively used to study P i transport (42). Expression analysis identified Npt2a and Npt2c at mRNA and protein levels (25,27). In addition, OK cells express functional PTH receptors and can respond to changes in P i content in the medium by modulating P i transport activity and Npt2a abundance (6,15).…”

Section: Introductionmentioning

confidence: 99%

PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies

Thomas

Xue

Tomilin

et al. 2020

American Journal of Physiology-Renal Physiology

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show abstract

“…Our unpublished observations also showed that PF-06869206 reduced plasma P i levels in mice fed a high P i diet. However, both studies [ 40 , 41 ] independently confirmed the specificity of these effects by using Npt2a −/− mice. Three-day treatment of rats with BAY-767 resulted in ∼20% lower plasma P i levels at 10 mg kg −1 [ 40 ].…”

Section: Effects Of Npt2a Inhibition On Plasma P I ...mentioning

confidence: 96%

“…The inhibitory kinetics of PF-06869206 were also studied by our group in OK cells which endogenously express Npt2a, Npt2c, Pit1 and Pit2 and are a commonly used model to study electrolyte and P i transport in the proximal tubule [41][42][43]. In OK cells, PF-06869206 caused a dose-dependent inhibition of Na + -dependent 32 P i uptake (IC 50 ∼1 mmol L −1 ), reaching a maximum inhibitory effect of ∼70% at 100 mmol L −1 .…”

Section: Development Of Npt2a Inhibitors -In Vitro Studiesmentioning

confidence: 99%

Npt2a as a target for treating hyperphosphatemia

Thomas

Rieg

2022

Biochemical Society Transactions

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Hyperphosphatemia results from an imbalance in phosphate (Pi) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral Pi binder and dietary Pi restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma Pi levels. In addition, a paradoxical increase in expression of intestinal Pi transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/Pi cotransporter 2a (Npt2a), responsible for ∼70% of Pi reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary Pi excretion consequently lowering plasma Pi and PTH levels. Additionally, increases in urinary excretions of Na+, Cl− and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on Pi homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.

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“…Kidney plays an important role in PO 4 homeostasis. About 80% of the filtered PO 4 is reabsorbed through specific sodium-phosphate cotransporters (NaPi II a and II c ) located in the proximal tubule [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

2020

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Background: phosphate homeostasis is mediated through complex counter regulatory feedback balance between parathyroid hormone, FGF-23 and 1,25(OH)2D. Both parathyroid hormone and FGF-23 regulate proximal tubular phosphate excretion through signaling on sodium-phosphate cotransporters II a and II c. However, the interaction between these hormones on phosphate excretion is not clearly understood. We performed the present study to evaluate whether the existence of sufficient parathyroid hormone is necessary for full phosphaturic function of FGF-23 or not. Methods: In this case-control study, 19 patients with hypoparathyroidism and their age-and gender-matched normal population were enrolled. Serum calcium, phosphate, alkaline phosphatase,parathyroid hormone, FGF-23, 25(OH)D, 1,25(OH)2D and Fractional excretion of phosphorous were assessed and compared between the two groups, using SPSS software. Results: The mean serum calcium and parathyroid hormone level was significantly lower in hypoparathyroid patients in comparison with the control group (P < 0.001 and P < 0.001, respectively). We found high serum level of phosphate and FGF-23 in hypoparathyroid patients compared to the control group (P < 0.001 and P < 0.001, respectively). However, there was no significant difference in Fractional excretion of phosphorous or 1,25OH2D level between the two groups. There was a positive correlation between serum FGF-23 and Fractional excretion of phosphorous just in the normal individuals (P < 0.001, r = 0.79). Conclusions: Although the FGF-23 is a main regulator of urinary phosphate excretion but the existence of sufficient parathyroid hormone is necessary for the full phosphaturic effect of FGF-23.

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Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney

Cited by 10 publications

References 38 publications

PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies

PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies

Npt2a as a target for treating hyperphosphatemia

Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

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Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney

Cited by 10 publications

References 38 publications

PF-06869206 is a selective inhibitor of renal Pitransport: evidence from in vitro and in vivo studies

PF-06869206 is a selective inhibitor of renal Pitransport: evidence from in vitro and in vivo studies

Npt2a as a target for treating hyperphosphatemia

Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

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PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies

PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies