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

Capuano, Paola; Stange, Gerti; Mühlemann, Reto; Murer, Heini; Biber, Jürg; Wagner, Carsten A.

doi:10.1007/s00424-013-1298-9

Cited by 36 publications

(37 citation statements)

References 62 publications

(84 reference statements)

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“…NaPi-IIa expression and FePO 4 2 increased to the same extent in proteinuric rats subjected to a normal-or a high-phosphate diet, indicating that adaptation to a highphosphate diet is not fully impaired because it may not rely only on FGF-23. 34 We observed that after a phosphate load, control rats did not display residual apical NaPi-IIa labeling by immunofluorescence ( Figure 3F). In phosphate-loaded proteinuric rats, NaPi-IIa was also less apparent at the apical membrane but could still be seen in some proximal tubule S1 segments of the juxtamedullary region ( Figure 3F).…”

Section: Albuminuria Is Associated With Higher Plasmamentioning

confidence: 80%

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Seigneux

Courbebaisse

Rutkowski

et al. 2015

Journal of the American Society of Nephrology

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Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria$300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2a, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.

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Section: Albuminuria Is Associated With Higher Plasmamentioning

confidence: 80%

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Seigneux

Courbebaisse

Rutkowski

et al. 2015

Journal of the American Society of Nephrology

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“…However, there are conflicting data regarding the sequence of events triggered by high dietary Pi as well as the nature of the trigger itself. PTH may have a key role in the acute renal response, with other hormones coming into play only later on, 23,[32][33][34] but the presence of yet-unidentified intestinal factor(s) stimulating renal Pi excretion independent from PTH has been proposed. 22 Here, we administered a Pi load to rats both intravenously (to bypass the gastrointestinal tract) and intragastrically and compared the acute responses in intact and PTX animals.…”

Section: Discussionmentioning

confidence: 99%

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

Thomas

Bettoni

Knöpfel

et al. 2016

JASN

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Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH)2-vitamin D3, and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but not gastric Pi loading in parathyroidectomized rats also led to higher creatinine clearance and lower plasma calcium levels but did not reduce the expression or activity of Pi transporters. This evidence suggests that an intravenous or intestinal Pi bolus causes rapid phosphaturia through mechanisms requiring PTH and downregulation of renal Pi transporters but does not support a role of the intestine in stimulating renal clearance of Pi. ABSTRACTPhosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH) 2 -vitamin D 3 , and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but no...

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“…PTH values showed a high degree of intragroup variability. We reported recently that the levels of this hormone change very quickly in response to switches in dietary P i (8). At the end of the sucrose/Doxydrinking protocol, animals were housed in single metabolic cages and food intake was closely monitored.…”

Section: Napi-iia Actinmentioning

confidence: 99%

Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice

Myakala

Motta

Murer

et al. 2014

American Journal of Physiology-Renal Physiology

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. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol 306: F833-F843, 2014. First published February 19, 2014 doi:10.1152/ajprenal.00133.2013.-The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/ SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of P i whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary P i, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney. phosphate homeostasis; epithelial transport; renal proximal tubules; SLC34 cotransporters INORGANIC PHOSPHATE (P I ) IS an essential anion that is required for a wide variety of molecular and cellular processes. In mammals, the concentration of P i in plasma remains within a relative tightly controlled range (0.8 -1.4 mM in humans). This control is executed by organs responsible for P i absorption/ excretion (intestine and kidneys), P i storage (bones), as well as production and secretion of regulatory factors (kidneys, bones, and parathyroid glands; for a review, see Ref. 5). However, the final control of P i homeostasis depends on the kidneys as they can adjust the urinary excretion of the anion to the body's specific requirements. The importance of the kidney in this process is highlighted by the deleterious consequences of both renal wasting and retention of the anion. Thus renal loss of P i leads primarily to skeletal deformities whereas hyperphosphatemia is implicated in vascular calcification and mortality in end-stage kidney disease (for a review, see Ref.2). The renal epithelia express at least three Na-dependent P i cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2 (for a review, see Ref. 14). These cotransporters are expressed in the brush-borde...

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

Cited by 36 publications

References 62 publications

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Acute Adaption to Oral or Intravenous Phosphate Requires Parathyroid Hormone

Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice

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