Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate

Giral, Héctor; Caldas, Yupanqui; Sutherland, Earl W.; Wilson, Paul; Breusegem, Sophia Y.; Barry, Nicolas P. E.; Blaine, Judith; Jiang, Tao; Wang, Xiaoxin X.; Levi, Moshe

doi:10.1152/ajprenal.00279.2009

Cited by 138 publications

(225 citation statements)

References 33 publications

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“…6,15 Multiple studies provide indirect evidence that Npt2b may also participate in CKD-associated hyperphosphatemia. 6,11,13,[16][17][18] To directly assess the therapeutic potential of targeting Npt2b, we evaluated the long-term effect of Npt2b deletion in a chronic CKD model. Using a modified adenine model in which progression of renal failure was limited by adenine withdrawal while allowing development of hyperphosphatemia and high turnover bone disease, we confirmed sustained decrease in serum phosphate levels in the Npt2b 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

“…This is in line with recent studies demonstrating post-transcriptional changes in Npt2b after acute alterations in dietary phosphate intake. 18 It is well known that the key hormones regulating calcium and phosphate homeostasis become dysregulated in CKD. As expected, serum PTH levels were equivalently elevated in uremic WTand Npt2b 2/2 mice ( Figure 5A).…”

Section: Discussionmentioning

confidence: 99%

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Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

Schiavi

Tang

Bracken

et al. 2012

Journal of the American Society of Nephrology

106

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The incidence of cardiovascular events and mortality strongly correlates with serum phosphate in individuals with CKD. The Npt2b transporter contributes to maintaining phosphate homeostasis in the setting of normal renal function, but its role in CKD-associated hyperphosphatemia is not well understood. Here, we used adenine to induce uremia in both Npt2b-deficient and wild-type mice. Compared with wild-type uremic mice, Npt2b-deficient uremic mice had significantly lower levels of serum phosphate and attenuation of FGF23. Treating Npt2b-deficient mice with the phosphate binder sevelamer carbonate further reduced serum phosphate levels. Uremic mice exhibited high turnover renal osteodystrophy; treatment with sevelamer significantly decreased the number of osteoclasts and the rate of mineral apposition in Npt2b-deficient mice, but sevelamer did not affect bone formation and rate of mineral apposition in wild-type mice. Taken together, these data suggest that targeting Npt2b in addition to using dietary phosphorus binders may be a therapeutic approach to modulate serum phosphate in CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

Schiavi

Tang

Bracken

et al. 2012

Journal of the American Society of Nephrology

106

View full text Add to dashboard Cite

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“…In contrast, in weaning animals, the achievement of a positive external balance is dependent on intestinal absorption and the ability of the kidneys to reclaim filtered P i . Little P i is lost in the feces, reflecting its extensive absorption, a process stimulated by dietary P i deprivation and 1,25(OH) 2 (9,34,38,41).…”

Section: Discussionmentioning

confidence: 99%

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

Ohi

Hanabusa

Ueda

et al. 2011

American Journal of Physiology-Renal Physiology

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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.

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“…More recent data also implicate members of the SLC20 family, or type III transporters, specifically PiT1 and PiT2, initially identified as retroviral receptors, in the intestinal and renal P i transport (26). Contrary to initial findings, they are now believed to be expressed at the intestinal (PiT1) (40) and renal brush border membrane (BBM) (PiT2) (106).…”

Section: Intestinal and Renal P I (Re)absorptionmentioning

confidence: 95%

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

Ghishan

Kiela

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ghishan FK, Kiela PR. Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases. Am J Physiol Gastrointest Liver Physiol 300: G191-G201, 2011. First published November 18, 2010 doi:10.1152/ajpgi.00496.2010.-Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1␤, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammationassociated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD.bone mineral density; Crohn's disease; osteopenia; osteoporosis; ulcerative colitis INFLAMMATORY BOWEL DISEASES (IBDs) represent a group of chronic inflammatory disorders of the intestinal tract that to this date remains idiopathic. More recent basic and clinical research indicates that the chronic inflammatory reaction of the intestinal mucosa is directed against the gut microbiota in individuals with genetic and/or environmental susceptibilities. Disease onset occurs typically during young adulthood (25-35 yr), although ϳ20 -25% of cases are diagnosed during childhood (93). On a clinical basis, two major subtypes of IBD are defined as Crohn's disease (CD), which potentially affects any part of the gastrointestinal tract from the mouth to the anus, and ulcerative colitis (UC), an inflammatory condition limited to the colonic mucosa. However, IBD does not affect just a single organ and should be considered a systemic disease with several extraintestinal manifestations, which occur in a large proportion of IBD patients (60). Osteopenia and osteoporosis are two of the more common extraintestinal symptoms with a general consensus that IBD patients are at a significantly higher risk of developing metabolic bone disease and low bone mineral density (BMD) than the healthy subjects. The relative risk of fractur...

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Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate

Cited by 138 publications

References 33 publications

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

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

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

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Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate

Cited by 138 publications

References 33 publications

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

Npt2b Deletion Attenuates Hyperphosphatemia Associated with CKD

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

Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases

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Product

Resources

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