Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules

Baum, Michel; Schiavi, Susan C.; Dwarakanath, Vangipuram; Quigley, Raymond

doi:10.1111/j.1523-1755.2005.00506.x

Cited by 135 publications

(93 citation statements)

References 38 publications

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“…7,21,22 In the face of hyperphosphatemia, serum PTH was suppressed, whereas FGF23 was increased in Ksp-KL 2/2 mice on a regular diet, suggesting that FGF23 may either respond earlier or play a more dominant role than PTH in regulating phosphate transport during chronic hyperphosphatemia. The reduction in PTH found in Ksp-KL 2/2 mice could could either be caused by higher systemic calcium levels or the fact that FGF23 inhibits PTH synthesis and secretion by directly targeting the parathyroid glands.…”

Section: /2mentioning

confidence: 99%

“…3 Furthermore, Klotho forms a specific receptor complex with fibroblast growth factor receptor 1c (FGFR1c) that transmits signaling of the circulating hormone FGF23. 4 Renal FGF23-Klotho signaling leads to internalization of Npt2a and Npt2c [5][6][7] and alterations in Cyp27B1 and Cyp24A1 transcripts encoding regulatory enzymes in vitamin D metabolism. 8 At the systemic level, this translates into a reduction of serum phosphate and 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 …”

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confidence: 99%

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Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

Olauson

Lindberg

Amin

et al. 2012

Journal of the American Society of Nephrology

135

112

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Renal Klotho controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone fibroblast growth factor-23 (FGF23). Klotho null mice have a markedly abnormal phenotype. We sought to determine effects of renal-specific and partial deletion of Klotho to facilitate investigation of its roles in health and disease. We generated a mouse model with partial deletion of Klotho in distal tubular segments (Ksp-KL 2/2 ).In contrast to Klotho null mice, Ksp-KL 2/2 mice were fertile, had a normal gross phenotype, and did not have vascular or tubular calcification on renal histology. However, Ksp-KL 2/2 mice were hyperphosphatemic with elevated FGF23 levels and abundant expression of the sodium-phosphate cotransporter Npt2a at the brush border membrane. Serum calcium and 1,25-dihydroxyvitamin D 3 levels were normal but parathyroid hormone levels were decreased. TRPV5 protein was reduced with a parallel mild increase in urinary calcium excretion. Renal expression of vitamin D regulatory enzymes and vitamin D receptor was higher in Ksp-KL 2/2 mice than controls, suggesting increased turnover of vitamin D metabolites and a functional increase in vitamin D signaling. There was a threshold effect of residual renal Klotho expression on FGF23: deletion of .70% of Klotho resulted in FGF23 levels 30-250 times higher than in wild-type mice. A subgroup of Ksp-KL 2/2 mice with normal phosphate levels had elevated FGF23, suggesting a Klothoderived renal-bone feedback loop. Taken together, renal FGF23-Klotho signaling, which is disrupted in CKD, is essential for homeostatic control of mineral metabolism.

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Section: /2mentioning

confidence: 99%

mentioning

confidence: 99%

Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

Olauson

Lindberg

Amin

et al. 2012

Journal of the American Society of Nephrology

135

112

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“…The pathway by which FGF23 regulates NaPi-IIa function and expression in the proximal tubule is controversial. FGF23 may act either indirectly on the proximal tubule via direct stimulation of a MAPK dependent pathway in the distal tubule [22] or may directly elicit an intracellular signaling cascade in the proximal tubule [3,6,24].…”

Section: Napi-iia Is Upregulated Despite Persistently High Fgf23 Levelmentioning

confidence: 99%

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

Capuano

Stange

Mühlemann

et al. 2013

Pflugers Arch - Eur J Physiol

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Renal reabsorption of inorganic phosphate (Pi) is mediated by the phosphate transporters NaPi-IIa, NaPi-IIc, and Pit-2 in the proximal tubule brush border membrane (BBM). Dietary Pi intake regulates these transporters; however, the contribution of the specific isoforms to the rapid and slow phase is not fully clarified. Moreover, the regulation of PTH and FGF23, two major phosphaturic hormones, during the adaptive phase has not been correlated. C57/BL6 and NaPi-IIa(-/-) mice received 5 days either 1.2 % (HPD) or 0.1 % (LPD) Pi-containing diets. Thereafter, some mice were acutely switched to LPD or HPD. Plasma Pi concentrations were similar under chronic diets, but lower when mice were acutely switched to LPD. Urinary Pi excretion was similar in C57/BL6 and NaPi-IIa(-/-) mice under HPD. During chronic LPD, NaPi-IIa(-/-) mice lost phosphate in urine compensated by higher intestinal Pi absorption. During the acute HPD-to-LPD switch, NaPi-IIa(-/-) mice exhibited a delayed decrease in urinary Pi excretion. PTH was acutely regulated by low dietary Pi intake. FGF23 did not respond to low Pi intake within 8 h whereas the phospho-adaptator protein FRS2 necessary for FGF-receptor cell signaling was downregulated. BBM Pi transport activity and NaPi-IIa but not NaPi-IIc and Pit-2 abundance acutely adapted to diets in C57/BL6 mice. In NaPi-IIa(-/-), Pi transport activity was low and did not adapt. Thus, NaPi-IIa mediates the fast adaptation to Pi intake and is upregulated during the adaptation to low Pi despite persistently high FGF23 levels. The sensitivity to FGF23 may be regulated by adapting FRS2 abundance and phosphorylation. ABSTRACTRenal reabsorption of inorganic phosphate (Pi) is mediated by the phosphate transporters, NaPi-IIa, NaPi-IIc, and Pit-2 in the proximal tubule brush border membrane (BBM). Dietary Pi intake regulates these transporters, however, the contribution of the specific isoforms to the rapid and slow phase are not fully clarified.Moreover, the regulation of PTH and FGF23, two major phosphaturic hormones, during the adaptive phase has not been correlated. C57/BL6 and NaPi-IIa -/-mice received 5 days either 1.2 % (HPD) or 0.1% (LPD) Pi containing diets. Thereafter, some mice were acutely switched to LPD or HPD. Plasma Pi concentrations were similar under chronic diets, but lower when mice were acutely switched to LPD.Urinary Pi excretion was similar in C57/BL6 and NaPi-IIa -/-mice under HPD. During chronic LPD, NaPi-IIa -/-mice lost phosphate in urine compensated by higher intestinal Pi absorption. During the acute HPD-to-LPD switch, NaPi-IIa -/-mice exhibited a delayed decrease in urinary Pi excretion. PTH was acutely regulated by low dietary Pi intake. FGF23 did not respond to low Pi intake within 8 hours whereas the phosphoadaptator protein FRS2α necessary for FGF-receptor cell signaling was downregulated. BBM Pi transport activity and NaPi-IIa but not NaPi-IIc and Pit-2 abundance acutely adapted to diets in C57/BL6 mice. In NaPi-IIa -/-Pi transport activity was low and did not adapt. Th...

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“…Both inhibit proximal tubular sodium-dependent PO4 reabsorption (via Na/PO4 cotransport, NaPi2a and NaPi2c). 5,6 In addition, a-Klotho is a renal transmembrane and secreted protein that functions as an FGF-23 coreceptor and is phosphaturic independently of However, the relative roles of other phosphaturic agents, such as secreted frizzled related protein (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF-8 are not yet defined in humans.1,25(OH) 2 D, PTH, and FGF-23 regulate PO4 metabolism within a complex system of positive and negative feedback mechanisms (for review, see Bergwitz and Jüppner 8 ). Increases in plasma PO4 concentration stimulate PTH secretion, while proximal tubule 1a-hydroxylase and, therefore,…”

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confidence: 99%

mentioning

confidence: 99%

The Human Response to Acute Enteral and Parenteral Phosphate Loads

Scanni

vonRotz

Jehle

et al. 2014

Journal of the American Society of Nephrology

107

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The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; a-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads. Plasma phosphate (PO4) concentration is regulated within narrow limits and is the result of intestinal absorption, influx into and efflux from bone, renal excretion, and modest intestinal secretion. 1 Rapid changes in transcellular distribution are effected primarily by systemic acid-base equilibrium and hormones such as insulin and catecholamines. 2 1,25(OH) 2 D stimulates intestinal PO4 absorption, 4 while parathyroid hormone (PTH) and osteocytederived fibroblast growth factor-23 (FGF-23) are the best-characterized phosphaturic factors. Both inhibit proximal tubular sodium-dependent PO4 reabsorption (via Na/PO4 cotransport, NaPi2a and NaPi2c). 5,6 In addition, a-Klotho is a renal transmembrane and secreted protein that functions as an FGF-23 coreceptor and is phosphaturic independently of However, the relative roles of other phosphaturic agents, such as secreted frizzled related protein (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF-8 are not yet defined in humans.1,25(OH) 2 D, PTH, and FGF-23 regulate PO4 metabolism within a complex system of positive and negative feedback mechanisms (for review, see Bergwitz and Jüppner 8 ). Increases in plasma PO4 concentration stimulate PTH secretion, while proximal tubule 1a-hydroxylase and, therefore,

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Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules

Abstract: These data demonstrate that the inhibition of phosphate transport by FGF23R176Q in vitro requires heparin. The action of FGF23R176Q is associated with a reduction in BBMV NaPi-2A protein abundance.

Cited by 135 publications

References 38 publications

Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

Targeted Deletion of Klotho in Kidney Distal Tubule Disrupts Mineral Metabolism

The phosphate transporter NaPi-IIa determines the rapid renal adaptation to dietary phosphate intake in mouse irrespective of persistently high FGF23 levels

The Human Response to Acute Enteral and Parenteral Phosphate Loads

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