Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Hoag, H; Martel, Josée; Gauthier, Claude; Tenenhouse, Harriet S.

doi:10.1172/jci7103

Cited by 82 publications

(71 citation statements)

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“…The type IIa transporter-depleted mRNA contained a mRNA species that showed some sequence homology to the type IIa transporter encoding message. This conclusion is compatible with the observation that young type IIa (Npt2) knock-out mice lacking type IIa mRNA and protein retain the capacity to reabsorb P i at a rate that cannot be explained by the presence of type I and III Na/P i transporter (8,9). In the present study, we isolated a growthrelated type II Na/P i cotransporter in human and rat kidneys.…”

supporting

confidence: 90%

Growth-related Renal Type II Na/Pi Cotransporter

Segawa

Kaneko

Takahashi

et al. 2002

Journal of Biological Chemistry

279

348

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Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na ؉ -dependent inorganic phosphate (P i ) cotransporter (type IIc). Microinjection of type IIc cRNA into Xenopus oocytes demonstrated sodium-dependent P i cotransport activity. Affinity for P i was 0.07 mM in 100 mM Na ؉ . The transport activity was dependent on extracellular pH. In electrophysiological studies, type IIc Na/P i cotransport was electroneutral, whereas type IIa was highly electrogenic. In Northern blotting analysis, the type IIc transcript was only expressed in the kidney and highly in weaning animals. In immunohistochemical analysis, the type IIc protein was shown to be localized at the apical membrane of the proximal tubular cells in superficial and midcortical nephrons of weaning rat kidney. Hybrid depletion experiments suggested that type IIc could function as a Na/P i cotransporter in weaning animals, but its role is reduced in adults. The finding of the present study suggest that the type IIc is a growth-related renal Na/P i cotransporter, which has a high affinity for P i and is electroneutral.

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confidence: 90%

Growth-related Renal Type II Na/Pi Cotransporter

Segawa

Kaneko

Takahashi

et al. 2002

Journal of Biological Chemistry

279

348

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“…At this time point, serum P i levels were lower than in the control group and the 7-day acidosis group. However, it is unclear whether this small fall in serum P i levels is enough to serve as a stimulus for intestinal adaptation, because much lower serum P i levels during dietary P i reduction have been found, which in turn stimulated NaPiIIa or NaPi-IIb expression (19). At the moment, it remains to be examined whether such a small fall in serum P i levels stimulates NaPi-IIb protein expression without elevating mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na⁺-dependent phosphate absorption and expression of the Na⁺-P_i cotransporter NaPi-IIb in small intestine

Stauber¹,

Radanovic²,

Stange³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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During metabolic acidosis, P i serves as an important buffer to remove protons from the body. Pi is released from bone together with carbonate buffering protons in blood. In addition, in the kidney, the fractional excretion of phosphate is increased allowing for the excretion of more acid equivalents in urine. The role of intestinal P i absorption in providing Pi to buffer protons and compensating for loss from bone during metabolic acidosis has not been clarified yet. Inducing metabolic acidosis (NH 4Cl in drinking water) for 2 or 7 days in mice increased urinary fractional P i excretion twofold, whereas serum Pi levels were not altered. Na ϩ -dependent Pi transport in the small intestine, however, was stimulated from 1.89 Ϯ 3.22 to 40.72 Ϯ 11.98 pmol/mg protein (2 days of NH 4Cl) in brush-border membrane vesicles prepared from total small intestine. Similarly, the protein abundance of the Na ϩ -dependent phosphate cotransporter NaPi-IIb in the brush-border membrane was increased 5.3-fold, whereas mRNA levels remained stable. According to immunohistochemistry and real-time PCR NaPi-IIb expression was found to be mainly confined to the ileum in the small intestine, and this distribution was not altered during metabolic acidosis. These results suggest that the stimulation of intestinal P i absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone. phosphate SEVERAL MECHANISMS CONTRIBUTE to the buffering and elimination of excessive protons and acid equivalents during metabolic acidosis. Besides respiration, increased release of buffer substances from bone and stimulated reabsorption of bicarbonate and increased excretion of protons by the kidneys are the major mechanisms to restore acid-base balance (11, 16). Excretion of protons by the kidney requires so called titratable acids, i.e., ammonia, citrate, and phosphate, buffering protons in urine in the collecting duct and thus increasing the maximal acid excretion rate (16). The renal excretion of ammonia and phosphate is highly increased during metabolic acidosis, whereas excretion of citrate is decreased (3). Ammonia (NH 3 ) is synthetized from glutamine metabolism in the kidney proximal tubule in response to metabolic acidosis (27). In addition, it is thought that inhibition of renal reabsorption of phosphate contributes mainly to increased phosphate excretion (1). In a rat model for metabolic acidosis, a decrease in mRNA and protein of the major Na ϩ -P i cotransporter NaPi-IIa as well as in Na ϩ -dependent P i uptake into brush border membrane (BBM) vesicles (BBMV) has been found (1). Systemic P i levels are only slightly decreased during metabolic acidosis, an effect that has been attributed to the acid-stimulated release of P i from bone together with Ca 2ϩ and carbonate (23). Indeed, the release of phosphate from bone during short-and long-term metabolic acidosis in in vivo and in in vitro models has been extensively documented a...

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“…Antigen antibody complexes were visualized by chemiluminescence (ECL kit, Amersham Biosciences, Montreal, Quebec). The abundance of Npt2a cotransporter protein, relative to that of actin, was quantitated using FujiScan software as described (10). Activation of the mitogen-activated protein kinase (MAPK) pathway was determined by detection of phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 proteins in cell lysates from MCT cells treated with FGF-23(R176Q) (100 ng/ml) for 1-120 min.…”

Section: Western Blot Analysismentioning

confidence: 99%

Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro

Perwad

Zhang²,

Tenenhouse³

et al. 2007

American Journal of Physiology-Renal Physiology

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263

197

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August 15, 2007; doi:10.1152/ajprenal.00463.2006) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH) 2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/P i) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 g/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P Ͻ 0.001) in brush-border membrane (BBM) Na/P i cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/P i cotransporter protein in BBM. Multiple injections (6, 12, and 24 g/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1␣-hydroxylase mRNA (P Ͻ 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1␣-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1␣-hydroxylase mRNA with a maximum suppression of 37% (P Ͻ 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1␣-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1␣-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1␣-hydroxylase gene expression via activation of the ERK1/2 signaling pathway. bone and mineral homeostasis; hypophosphatemic syndromes FIBROBLAST GROWTH FACTOR-23 (FGF-23), a bone-derived circulating peptide, is an important regulator of phosphorus and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] metabolism and is required for maintenance of normal bone and mineral homeostasis. An excess of FGF-23 has been linked to the pathogenesis of tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets (4,12,21,29,33). These hypophosphatemic syndromes share common clinical and laboratory features which include rickets and osteomalacia, hypophosphatemia due to renal phosphate (P i ) wasting, inappropriately low serum 1,25(OH) 2 D concentrations, and greatly increased serum FGF-23 concentrations. That excess circulating FGF-23 contributes to the pathogenesis of these disorders is supported by observations that administration of recombinant FGF-23 or its overexpression in animals induces hypophosphatemia and inhibition of sodium (Na)-dependent P i (Na/P i ) cotransport in renal brush-border membrane (BBM) vesicles (1,19,29). FGF-23 suppresses the renal production of 1,25(OH) 2 D by suppressin...

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Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Cited by 82 publications

References 50 publications

Growth-related Renal Type II Na/Pi Cotransporter

Growth-related Renal Type II Na/Pi Cotransporter

Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na⁺-dependent phosphate absorption and expression of the Na⁺-P_i cotransporter NaPi-IIb in small intestine

Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro

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Effects of Npt2 gene ablation and low-phosphate diet on renal Na+/phosphate cotransport and cotransporter gene expression

Cited by 82 publications

References 50 publications

Growth-related Renal Type II Na/Pi Cotransporter

Growth-related Renal Type II Na/Pi Cotransporter

Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na+-dependent phosphate absorption and expression of the Na+-Pi cotransporter NaPi-IIb in small intestine

Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro

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Regulation of Intestinal Phosphate Transport II. Metabolic acidosis stimulates Na⁺-dependent phosphate absorption and expression of the Na⁺-P_i cotransporter NaPi-IIb in small intestine