Sodium-Dependent Phosphate Cotransporters: Lessons from Gene Knockout and Mutation Studies

Miyamoto, Ken‐ichi; Haito-Sugino, Sakiko; Kudoh, Shoji; Ohi, Akiko; Nomura, Kazuki; Ito, Mikiko; Kuwahata, Masashi; Kido, Shinsuke; Tatsumi, Sawako; Kaneko, Ichiro; Segawa, Hiroko

doi:10.1002/jps.22614

Cited by 94 publications

(64 citation statements)

References 86 publications

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“…The SLC17 family includes 9 members, while SLC20 family has 3 members (one pseudo) and the SLC34 family also has 3 members. [20][21][22] Finally, therefore, we examined whether these transporters might be present within the untreated ear-pinnas of mice. As shown in Fig.…”

Section: Detection Of Phosphate Transporters Within Ear-pinnasmentioning

confidence: 99%

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Kiyama

Tsuchiya

Okada

et al. 2016

Biological & Pharmaceutical Bulletin

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Bisphosphonates (BPs) are used against diseases involving increased bone-resorption. Among BPs, nitrogencontaining BPs (N-BPs) have much stronger anti-bone-resorptive effects than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs carry the risk of inflammatory/necrotic effects, including osteonecrosis of jawbones. When injected into mouse ear-pinnas, N-BPs induce inflammatory/necrotic effects within the ear-pinna. We previously found that (a) the non-N-BPs clodronate and etidronate can reduce such side effects of N-BPs, and (b) phosphonoformate (an inhibitor of the phosphate transporters SLC20 and SLC34) can reduce the inflammatory/necrotic effects of zoledronate (the N-BP with the highest reported risk of side effects). However, it is not clear (i) whether phosphonoformate can reduce the side effects of other N-BPs, too, and (ii) whether other phosphonocarboxylates have such inhibitory effects. Here, using the mouse ear-pinna model, we compared the effects of etidronate, clodronate, and four phosphonocarboxylates on the inflammatory/necrotic effects of N-BPs of the alkyl type (alendronate) or cyclic type (zoledronate and minodronate). Like phosphonoformate, the other three phosphonocarboxylates protected against the inflammatory/necrotic effects of all the N-BPs. The protective potencies were clodronate>etidronate>phosphonoacetate>phosphonoformate> phosphonopropionate>phosphonobutyrate. With a similar order of potencies, these agents reduced the amount of 3 H-alendronate retained within the ear-pinna after its injection therein. The mRNAs of SLC20 and SLC34 were detected in untreated ear-pinnas. These findings suggest that the inhibition of phosphate transporters by phosphonocarboxylates, as well as by etidronate and clodronate, might be a useful preventive strategy against the side effects of both alkyl-and cyclic-type N-BPs.

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Section: Detection Of Phosphate Transporters Within Ear-pinnasmentioning

confidence: 99%

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Kiyama

Tsuchiya

Okada

et al. 2016

Biological & Pharmaceutical Bulletin

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“…1,14,30,31 Renal Phosphate Regulation Under normal physiologic conditions, the kidneys maintain serum phosphate balance by fine-tuning urinary phosphate excretion. Filtrated phosphate is reabsorbed in the renal proximal tubular epithelial cells using sodium-dependent phosphate (Na/Pi) cotransporters [32][33][34] (Figure 1). Although these cells contain three types of Na/Pi cotransporters, the type 2 cotransporter family that includes Na/Pi2a (encoded by the SLC34a1 gene) and NaPi2c (encoded by the SLC34a3 gene) is believed to be most active in renal phosphate uptake.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Brown

2015

BoneKEy Reports

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Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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“…Based on these findings it was assumed that NaPi-IIa has a major quantitative impact on renal reabsorption of P i . However, recent data suggest that NaPi-IIc may play more important role in humans (see 2.5.2) (Bergwitz et al, 2006;Miyamoto et al).…”

Section: Physiological Pathophysiological and Pharmaceutical Aspectsmentioning

confidence: 99%

Phosphate transporters of the SLC20 and SLC34 families

Forster

Hernando

Biber

et al. 2013

Molecular Aspects of Medicine

181

198

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Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology. AbstractTransport of inorganic phosphate (P i ) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na + -dependent, secondary-active cotransporters to transport P i across cell membranes. The SLC34 proteins are expressed in specific organs important for P i homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in P i reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates P i absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity,regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarises our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiologies and pharmacology.3

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Sodium-Dependent Phosphate Cotransporters: Lessons from Gene Knockout and Mutation Studies

Cited by 94 publications

References 86 publications

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Phosphate transporters of the SLC20 and SLC34 families

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