Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b+/− mice

2011 ◽  
Vol 301 (5) ◽  
pp. F1105-F1113 ◽  
Author(s):  
Akiko Ohi ◽  
Etsuyo Hanabusa ◽  
Otoya Ueda ◽  
Hiroko Segawa ◽  
Naoshi Horiba ◽  
...  
Keyword(s):  
Inorganic Phosphate ◽  
Fibroblast Growth Factor 23 ◽  
High Plasma ◽  
Phosphate Binders ◽  
Ectopic Calcification ◽  
Activity Levels ◽  
Mrna Levels ◽  
Distal Intestine ◽  
Transporter Protein ◽  
Sodium Dependent

An inorganic phosphate (Pi)-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium-dependent Pi (Na/Pi) transport system is involved in intestinal Pi absorption and is regulated by several factors. The type II sodium-dependent Pi transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports Pi. In the present study, we analyzed the phenotype of Npt2b−/− and hetero+/− mice. Npt2b−/− mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b+/− mice showed hypophosphatemia and low urinary Pi excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)2D3 levels were significantly increased in Npt2b+/− mice compared with Npt2b+/+ mice. Npt2b mRNA levels were reduced to 50% that in Npt2b+/+ mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b+/− mice. At 20 wk of age, Npt2b+/− mice showed hypophosphaturia and reduced Na/Pi cotransport activity in the distal intestine. Npt2b+/+ mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b+/− mice treated with adenine had significantly reduced plasma Pi levels compared with Npt2b+/+ mice. Intestinal Npt2b protein and Na+/Pi transport activity levels were significantly lower in Npt2b+/− mice than in the Npt2b+/+ mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia.

scholarly journals Phosphate Transporter Regulator That Prevents Abnormal Hyperphosphatemia.

2021 ◽  
Author(s):  
Sumire Sasaki ◽  
Yuji Shiozaki ◽  
Ai Hanazaki ◽  
Megumi Koike ◽  
Kazuya Tanifuji ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Inorganic Phosphate ◽  
Fibroblast Growth Factor 23 ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Type Ii ◽  
Fibroblast Growth ◽  
Sodium Dependent ◽  
Fgf23 Concentration

Abstract Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), enhances urinary Pi excretion and prevents the onset of hyperphosphatemia. How FGF23 is induced from the bones by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of transporter-associated protein (TRAP), found in gene co-expression networks in NaPi2a and NaPi2c function. TRAP is localized in the renal proximal tubules and interacts with NaPi2a. In TRAP-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, TRAP-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in TRAP-KO mice. Thus, TRAP is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury.

Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice

2007 ◽  
Vol 292 (2) ◽  
pp. F769-F779 ◽  
Author(s):  
Hiroko Segawa ◽  
Setsuko Yamanaka ◽  
Yasue Ohno ◽  
Akemi Onitsuka ◽  
Kazuyo Shiozawa ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Fibroblast Growth Factor 23 ◽  
Colchicine Treatment ◽  
High Plasma ◽  
Wild Type ◽  
Phosphate Homeostasis ◽  
Sodium Dependent ◽  
In The Wild ◽  
Klotho Protein ◽  
Increased Activity

Recent studies have demonstrated that klotho protein plays a role in calcium/phosphate homeostasis. The goal of the present study was to investigate the regulation of Na-Pi cotransporters in klotho mutant (kl/kl) mice. The kl/kl mice displayed hyperphosphatemia, high plasma 1,25(OH)2D3 levels, increased activity of the renal and intestinal sodium-dependent Pi cotransporters, and increased levels of the type IIa, type IIb, and type IIc transporter proteins compared with wild-type mice. Interestingly, transcript levels of the type IIa/type IIc transporter mRNA abundance, but not transcripts levels of type IIb transporter mRNA, were markedly decreased in kl/kl mice compared with wild-type mice. Furthermore, plasma fibroblast growth factor 23 (FGF23) levels were 150-fold higher in kl/kl mice than in wild-type mice. Feeding of a low-Pi diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. Finally, feeding of a low-Pi diet resulted in increased type IIa Na-Pi cotransporter protein in the apical membrane in the wild-type mice, but not in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type IIa/IIc transporters rather than to intestinal Pi uptake.

scholarly journals Sodium-Dependent Phosphate Transporter Protein 1 Is Involved in the Active Uptake of Inorganic Phosphate in Nephrocytes of the Kidney and the Translocation of Pi Into the Tubular Epithelial Cells in the Outer Mantle of the Giant Clam, Tridacna squamosa

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuen K. Ip ◽  
Mel V. Boo ◽  
Jeslyn S. T. Poo ◽  
Wai P. Wong ◽  
Shit F. Chew
Keyword(s):  
Epithelial Cells ◽  
Inorganic Phosphate ◽  
Phosphate Transporter ◽  
Giant Clam ◽  
Tubular Epithelial Cells ◽  
Expression Levels ◽  
Transporter Protein ◽  
Giant Clams ◽  
Sodium Dependent ◽  
Tridacna Squamosa

Giant clams display light-enhanced inorganic phosphate (Pi) absorption, but how the absorbed Pi is translocated to the symbiotic dinoflagellates living extracellularly in a tubular system is unknown. They can accumulate Pi in the kidney, but the transport mechanism remains enigmatic. This study aimed to elucidate the possible functions of sodium-dependent phosphate transporter protein 1-homolog (PiT1-like), which co-transport Na+ and H2PO4–, in these two processes. The complete cDNA coding sequence of PiT1-like, which comprised 1,665 bp and encoded 553 amino acids (59.3 kDa), was obtained from the fluted giant clam, Tridacna squamosa. In the kidney, PiT1-like was localized in the plasma membrane of nephrocytes, and could therefore absorb Pi from the hemolymph. As the gene and protein expression levels of PiT1-like were up-regulated in the kidney during illumination, PiT1-like could probably increase the removal of Pi from the hemolymph during light-enhanced Pi uptake. In the ctenidial epithelial cells, PiT1-like had a basolateral localization and its expression was also light-dependent. It might function in Pi sensing and the absorption of Pi from the hemolymph when Pi was limiting. In the outer mantle, PiT1-like was localized in the basolateral membrane of epithelial cells forming the tertiary tubules. It displayed light-enhanced expression levels, indicating that the host could increase the translocation of Pi from the hemolymph into the tubular epithelial cells and subsequently into the luminal fluid to support increased Pi metabolism in the photosynthesizing dinoflagellates. Taken together, the accumulation of Pi in the kidney of giant clams might be unrelated to limiting the availability of Pi to the symbionts to regulate their population.

Downregulation of renal type IIa sodium-dependent phosphate cotransporter during lipopolysaccharide-induced acute inflammation

2014 ◽  
Vol 306 (7) ◽  
pp. F744-F750 ◽  
Author(s):  
Shoko Ikeda ◽  
Hironori Yamamoto ◽  
Masashi Masuda ◽  
Yuichiro Takei ◽  
Otoki Nakahashi ◽  
...  
Keyword(s):  
Time Course ◽  
Acute Inflammation ◽  
Fibroblast Growth Factor 23 ◽  
Critical Role ◽  
Calcium Excretion ◽  
Mrna Levels ◽  
Dihydroxyvitamin D ◽  
Sodium Dependent ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

The type IIa sodium-dependent phosphate cotransporter (Npt2a) plays a critical role in reabsorption of inorganic phosphate (Pi) by renal proximal tubular cells. Pi abnormalities during early stages of sepsis have been reported, but the mechanisms regulating Pi homeostasis during acute inflammation are poorly understood. We examined the regulation of Pi metabolism and renal Npt2a expression during lipopolysaccharide (LPS)-induced inflammation in mice. Dose-response and time-course studies with LPS showed significant increases of plasma Pi and intact parathyroid hormone (iPTH) levels and renal Pi excretion, while renal calcium excretion was significantly decreased. There was no difference in plasma 1,25-dihydroxyvitamin D levels, but the induction of plasma intact fibroblast growth factor 23 levels peaked 3 h after LPS treatment. Western blotting, immunostaining, and quantitative real-time PCR showed that LPS administration significantly decreased Npt2a protein expression in the brush border membrane (BBM) 3 h after injection, but there was no change in renal Npt2a mRNA levels. Moreover, tumor necrosis factor-α injection also increased plasma iPTH and decreased renal BBM Npt2a expression. Importantly, we revealed that parathyroidectomized rats had impaired renal Pi excretion and BBM Npt2a expression in response to LPS. These results suggest that the downregulation of Npt2a expression in renal BBM through induction of plasma iPTH levels alter Pi homeostasis during LPS-induced acute inflammation.

Diabetes, Diabetic Complications, and Phosphate Toxicity: A Scoping Review

2020 ◽  
Vol 16 (7) ◽  
pp. 674-689 ◽  
Author(s):  
Ronald B. Brown
Keyword(s):  
Scoping Review ◽  
Diabetic Complications ◽  
Inorganic Phosphate ◽  
Dietary Intervention ◽  
Neuronal Degeneration ◽  
Ectopic Calcification ◽  
Treatment And Prevention ◽  
Research Findings ◽  
Serum Inorganic Phosphate ◽  
Prevention Of Diabetes

This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate—phosphate toxicity—as a pathophysiological determinant of diabetes and diabetic complications. Phosphorus, an essential micronutrient, is closely linked to the cellular metabolism of glucose for energy production, and serum inorganic phosphate is often transported into cells along with glucose during insulin therapy. Mitochondrial dysfunction and apoptosis, endoplasmic reticulum stress, neuronal degeneration, and pancreatic cancer are associated with dysregulated levels of phosphate in diabetes. Ectopic calcification involving deposition of calcium-phosphate crystals is prevalent throughout diabetic complications, including vascular calcification, nephropathy, retinopathy, and bone disorders. A low-glycemic, low-phosphate dietary intervention is proposed for further investigations in the treatment and prevention of diabetes and related diabetic pathologies.

scholarly journals Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Egli-Spichtig ◽  
Martin Y. H. Zhang ◽  
Alfred Li ◽  
Eva Maria Pastor Arroyo ◽  
Nati Hernando ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Actin Polymerization ◽  
Fibroblast Growth Factor 23 ◽  
Wild Type ◽  
Vitamin D Metabolism ◽  
Endocrine Hormone ◽  
Dnase 1 ◽  
Sodium Dependent ◽  
Renal Tubular ◽  
High Phosphate

AbstractFibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

scholarly journals The Sodium-Dependent Inorganic Phosphate Transporter SLC34A1 (NaPi-IIa) Is Not Localized in the Mouse Brain

2011 ◽  
Vol 59 (9) ◽  
pp. 807-812 ◽  
Author(s):  
Max Larsson ◽  
Cecilie Morland ◽  
Irais Poblete-Naredo ◽  
Jürg Biber ◽  
Niels Christian Danbolt ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Inorganic Phosphate ◽  
Phosphate Transporter ◽  
Sodium Dependent

Proline utilization in Saccharomyces cerevisiae: analysis of the cloned PUT2 gene

1983 ◽  
Vol 3 (10) ◽  
pp. 1846-1856
Author(s):  
M C Brandriss
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Recombinant Dna ◽  
Fold Increase ◽  
Activity Levels ◽  
Mrna Levels ◽  
S1 Nuclease ◽  
Proline Utilization ◽  
Cloned Gene ◽  
His3 Gene ◽  
Specific Mrna

The PUT2 gene was isolated on a 6.5-kilobase insert of a recombinant DNA plasmid by functional complementation of a put2 (delta 1-pyrroline-5-carboxylate dehydrogenase-deficient) mutation in Saccharomyces cerevisiae. Its identity was confirmed by a gene disruption technique in which the chromosomal PUT2+ gene was replaced by plasmid DNA carrying the put2 gene into which the S. cerevisiae HIS3+ gene had been inserted. The cloned PUT2 gene was used to probe specific mRNA levels: full induction of the PUT2 gene resulted in a 15-fold increase over the uninduced level. The PUT2-specific mRNA was approximately 2 kilobases in length and was used in S1 nuclease protection experiments to locate the gene to a 3-kilobase HindIII fragment. When delta 1-pyrroline-5-carboxylate dehydrogenase activity levels were measured in strains carrying the original plasmid, as well as in subclones, similar induction ratios were found as compared with enzyme levels in haploid yeast strains. Effects due to increased copy number or position were also seen. The cloned gene on a 2 mu-containing vector was used to map the PUT2 gene to chromosome VIII.

Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum

1996 ◽  
Vol 271 (2) ◽  
pp. G377-G385 ◽  
Author(s):  
D. M. Christie ◽  
P. A. Dawson ◽  
S. Thevananther ◽  
B. L. Shneider
Keyword(s):  
Bile Acid ◽  
Rat Kidney ◽  
Membrane Vesicles ◽  
Mrna Levels ◽  
Sodium Dependent ◽  
Bile Acid Transporter ◽  
Old Rats ◽  
Acid Transporter ◽  
The Difference ◽  
And Function

An apical sodium-dependent bile acid transporter (ASBT) has recently been cloned and characterized in the rat ileum. Northern and Western blotting revealed both the ASBT mRNA and protein in rat kidney. The coding sequence of the kidney transcript was found to be identical to the previously cloned ileal ASBT. Indirect immunofluorescence studies localized the ASBT protein to the apical membrane of the renal proximal convoluted tubule. Kinetic analysis of sodium-dependent taurocholate uptake using membrane vesicles revealed a similar Michaelis-Menten constant value for taurocholate in the kidney and intestine. ASBT protein and function were present in the kidney but not the ileum from 7-day-old rats. On postnatal day 7, there was a sevenfold increase in ASBT steady-state mRNA levels in the kidney relative to the ileum, yet nuclear run-on assays revealed that the nascent transcription rates at this age were virtually the same. This suggests that the difference in the neonatal expression of the ASBT gene in the kidney and ileum may be in part due to differences in mRNA stability.

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