FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, −3, and −4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3−/− and FGFR4−/− null mice, and in conditional FGFR1−/− mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1−/−, FGFR3−/−, and FGFR4−/− mice and their wild-type counterparts. Administration of FGF23 to FGFR3−/− mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4−/− mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1−/− mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

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Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00460.2012 ◽

2013 ◽

Vol 304 (3) ◽

pp. E310-E320 ◽

Cited By ~ 74

Author(s):

Stephen J. Quinn ◽

Alex R. B. Thomsen ◽

Jian L. Pang ◽

Lakshmi Kantham ◽

Hans Bräuner-Osborne ◽

...

Keyword(s):

Serum Calcium ◽

Fibroblast Growth Factor 23 ◽

Threshold Level ◽

Serum Levels ◽

Serum Phosphorus ◽

Dihydroxyvitamin D ◽

Dietary Phosphorus ◽

Calcium Phosphorus ◽

Calcium And Phosphorus

Calcium and phosphorus homeostasis are highly interrelated and share common regulatory hormones, including FGF23. However, little is known about calcium's role in the regulation of FGF23. We sought to investigate the regulatory roles of calcium and phosphorus in FGF23 production using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR; PTH-CaSR DKO). In wild-type, PTH KO, and PTH-CaSR DKO mice, elevation of either serum calcium or phosphorus by intraperitoneal injection increased serum FGF23 levels. In PTH KO and PTH-CaSR DKO mice, however, increases in serum phosphorus by dietary manipulation were accompanied by severe hypocalcemia, which appeared to blunt stimulation of FGF23 release. Increases in dietary phosphorus in PTH-CaSR DKO mice markedly decreased serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] despite no change in FGF23, suggesting direct regulation of 1,25(OH)2D3 synthesis by serum phosphorus. Calcium-mediated increases in serum FGF23 required a threshold level of serum phosphorus of about 5 mg/dl. Analogously, phosphorus-elicited increases in FGF23 were markedly blunted if serum calcium was less than 8 mg/dl. The best correlation between calcium and phosphorus and serum FGF23 was found between FGF23 and the calcium × phosphorus product. Since calcium stimulated FGF23 production in the PTH-CaSR DKO mice, this effect cannot be mediated by the full-length CaSR. Thus the regulation of FGF23 by both calcium and phosphorus appears to be fundamentally important in coordinating the serum levels of both mineral ions and ensuring that the calcium × phosphorus product remains within a physiological range.

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Regulation of 1,25 (OH)2D synthesis in hypoparathyroidism and pseudohypoparathyroidism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.255.5.e730 ◽

1988 ◽

Vol 255 (5) ◽

pp. E730-E736

Author(s):

N. A. Breslau ◽

R. S. Weinstock

Keyword(s):

Serum Phosphorus ◽

Phosphorus Concentration ◽

Parathyroid Hormone Receptor ◽

Cyclic Monophosphate ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Complex Patients ◽

Phosphorus Deprivation ◽

Parathyroid Extract ◽

Phosphorus Levels

We examined the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] synthesis in patients with hypoparathyroidism (n = 5) and pseudohypoparathyroidism (n = 5) by administration of parathyroid extract (PTE) and N6,O2-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP) and by phosphorus deprivation with antacids. In response to PTE, patients with hypoparathyroidism increased serum 1,25(OH)2D from 17 +/- 5 to 30 +/- 5 (SD) pg/ml (P less than 0.01). An approximate doubling of the 1,25(OH)2D concentration also occurred following dbcAMP infusion or phosphorus deprivation (serum phosphorus 4.4 +/- 0.5 to 2.6 +/- 1.1, P less than 0.01). Serum phosphorus and 1,25(OH)2D concentrations were inversely correlated (r = -0.73, P less than 0.001). Patients with pseudohypoparathyroidism had negligible responses to PTE with respect to urinary adenosine 3', 5'-cyclic monophosphate excretion, serum phosphorus concentration, or 1,25(OH)2D synthesis. They did show a rise in serum 1,25(OH)2D from 17 +/- 4 to 44 +/- 5 pg/ml (P less than 0.001) in response to dbcAMP infusion. During phosphorus deprivation, serum phosphorus decreased from 4.1 +/- 0.8 to 3.2 +/- 1.2 mg/dl (P less than 0.05), but there was no change in serum 1,25(OH)2D concentration or any correlation between serum phosphorus and 1,25(OH)2D levels. Although reduction in mean serum phosphorus levels was generally not as great in patients with pseudohypoparathyroidism, one such patient attained serum phosphorus of 1.2 mg/dl and still did not increase serum 1,25(OH)2D concentration. In addition to an abnormal parathyroid hormone receptor-adenylate cyclase complex, patients with pseudohypoparathyroidism appear to have an abnormal renal 1 alpha-hydroxylase, which does not respond appropriately to phosphate deprivation.

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71. Surprise, surprise: Glucocorticoids have a minor role compared to catecholamines and prostaglandins in mediating stress and surgery-induced In vivo suppression of NK activity

Brain Behavior and Immunity ◽

10.1016/j.bbi.2013.07.083 ◽

2013 ◽

Vol 32 ◽

pp. e21

Author(s):

S. Ben-Eliyahu ◽

E. Rosenne ◽

L. Sorski ◽

L. Shaashua ◽

E. Neeman ◽

...

Keyword(s):

Minor Role ◽

Nk Activity ◽

A Minor

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In Vitro and In Vivo Biology of Recombinant Adenovirus Vectors with E1, E1/E2A, or E1/E4 Deleted

Journal of Virology ◽

10.1128/jvi.72.3.2022-2032.1998 ◽

1998 ◽

Vol 72 (3) ◽

pp. 2022-2032 ◽

Cited By ~ 170

Author(s):

M. Lusky ◽

M. Christ ◽

K. Rittner ◽

A. Dieterle ◽

D. Dreyer ◽

...

Keyword(s):

Recombinant Adenovirus ◽

Virus Genome ◽

Minor Role ◽

Immunodeficient Mice ◽

Viral Genomes ◽

Viral Genes ◽

Adenovirus Vectors ◽

A Minor

ABSTRACT Isogenic, E3-deleted adenovirus vectors defective in E1, E1 and E2A, or E1 and E4 were generated in complementation cell lines expressing E1, E1 and E2A, or E1 and E4 and characterized in vitro and in vivo. In the absence of complementation, deletion of both E1 and E2A completely abolished expression of early and late viral genes, while deletion of E1 and E4 impaired expression of viral genes, although at a lower level than the E1/E2A deletion. The in vivo persistence of these three types of vectors was monitored in selected strains of mice with viral genomes devoid of transgenes to exclude any interference by immunogenic transgene-encoded products. Our studies showed no significant differences among the vectors in the short-term maintenance and long-term (4-month) persistence of viral DNA in liver and lung cells of immunocompetent and immunodeficient mice. Furthermore, all vectors induced similar antibody responses and comparable levels of adenovirus-specific cytotoxic T lymphocytes. These results suggest that in the absence of transgenes, the progressive deletion of the adenovirus genome does not extend the in vivo persistence of the transduced cells and does not reduce the antivirus immune response. In addition, our data confirm that, in the absence of transgene expression, mouse cellular immunity to viral antigens plays a minor role in the progressive elimination of the virus genome.

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Role of cytosolic rat liver aldehyde dehydrogenase in the oxidation of acetaldehyde during ethanol metabolism in vivo

Biochemical Journal ◽

10.1042/bj1520709 ◽

1975 ◽

Vol 152 (3) ◽

pp. 709-712 ◽

Cited By ~ 70

Author(s):

C J Eriksson ◽

M Marselos ◽

T Koivula

Keyword(s):

Aldehyde Dehydrogenase ◽

Oxidation Rate ◽

Ethanol Metabolism ◽

Minor Role ◽

Liver Cytosol ◽

A Minor ◽

Liver Aldehyde Dehydrogenase ◽

Phenobarbital Induction

The activity of a high-Km aldehyde dehydrogenase in the liver cytosol was increased by phenobarbital induction. No corresponding increase in the oxidation rate of acetaldehyde in vivo was found, and it is concluded that cytosolic aldehyde dehydrogenase plays only a minor role in the oxidation of acetaldehyde during ethanol metabolism.

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DC-SIGN Is the Major Mycobacterium tuberculosis Receptor on Human Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021468 ◽

2002 ◽

Vol 197 (1) ◽

pp. 121-127 ◽

Cited By ~ 428

Author(s):

Ludovic Tailleux ◽

Olivier Schwartz ◽

Jean-Louis Herrmann ◽

Elisabeth Pivert ◽

Mary Jackson ◽

...

Keyword(s):

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

Human Monocyte ◽

Mannose Receptor ◽

Intercellular Adhesion Molecule ◽

Minor Role ◽

Hla Dr ◽

A Minor ◽

Human Dendritic Cells

Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mϕs), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis–derived material was detected in CD14−HLA-DR+DC-SIGN+ cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN–mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.

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New Insight into Amphotericin B Resistance in Aspergillus terreus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01283-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1583-1588 ◽

Cited By ~ 40

Author(s):

Gerhard Blum ◽

Caroline Hörtnagl ◽

Emina Jukic ◽

Thomas Erbeznik ◽

Thomas Pümpel ◽

...

Keyword(s):

Amphotericin B ◽

Molecular Basis ◽

Aspergillus Terreus ◽

Minor Role ◽

Content Type ◽

Ergosterol Content ◽

Disseminated Aspergillosis ◽

A Minor

ABSTRACTAmphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared thein vivovirulence of an AMB-resistantAspergillus terreus(ATR) isolate with that of an AMB-susceptibleA. terreusisolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistancein vitroby comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. Thein vitrodata demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.

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Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation

Thrombosis and Haemostasis ◽

10.1160/th03-09-0588 ◽

2005 ◽

Vol 93 (06) ◽

pp. 1161-1167 ◽

Cited By ~ 50

Author(s):

Burcin Özüyaman ◽

Susanne Küsters ◽

Elisabeth Kirchhoff ◽

Rüdiger Scharf ◽

Jürgen Schrader ◽

...

Keyword(s):

Platelet Aggregation ◽

Thrombus Formation ◽

Surface Expression ◽

No Synthase ◽

Minor Role ◽

Endothelial No Synthase ◽

Tail Tip ◽

A Minor

SummaryEndothelial NO synthase (eNOS) expressed in the vascular en-dothelium or formed within platelets was postulated to inhibit platelet activation and aggregation. We have assessed the role of eNOS in platelet aggregation in vitro and in vivo by comparison of WT and eNOS-/- mice. Aggregometer studies revealed that collagen over a concentration range of 0.36–10 µg aggregated WT and eNOS-/- platelets to the same extent (10 µg: WT 86.7±4.7%, eNOS-/- 91±12%, n=6). Collagen treatment did not result in a significant increase in cGMP formation and VASP phosphorylation. Thrombin-induced P-selectin surface expression was unchanged in eNOS-/- platelets. In line with these findings no eNOS protein was detectable within the platelets of WT mice. In vivo, bleeding time after tail tip resection tended to be shorter in eNOS/- mice (WT: 116±35 s; eNOS-/- 109±37 s, n.s). Similarly, time to occlusion of the A.carotis after focal induction of thrombosis was 501±76 s (WT) and 457±95 s (eNOS-/-) (n.s.). These data demonstrate that eNOS-deficiency minimally affects platelet aggregation and is not associated with accelerated arterial thrombosis in vivo. Thus, in the mouse endothelial NO synthase does not play a major role in the autocrine modulation of platelet function and in thrombosis of conduit vessels in vivo.

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The Receptor-Dependent Actions of 1,25-Dihydroxyvitamin D Are Required for Normal Growth Plate Maturation in NPt2a Knockout Mice

Endocrinology ◽

10.1210/en.2010-0354 ◽

2010 ◽

Vol 151 (10) ◽

pp. 4607-4612 ◽

Cited By ~ 26

Author(s):

Susanne U. Miedlich ◽

Eric D. Zhu ◽

Yves Sabbagh ◽

Marie B. Demay

Keyword(s):

Vitamin D ◽

Growth Plate ◽

Fibroblast Growth Factor 23 ◽

Normal Growth ◽

Chondrocyte Apoptosis ◽

Apoptotic Pathway ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Hypertrophic Chondrocyte

Rickets is a growth plate abnormality observed in growing animals and humans. Rachitic expansion of the hypertrophic chondrocyte layer of the growth plate, in the setting of hypophosphatemia, is due to impaired apoptosis of these cells. Rickets is observed in humans and mice with X-linked hypophosphatemia that is associated with renal phosphate wasting secondary to elevated levels of fibroblast growth factor-23. Rickets is also seen in settings of impaired vitamin D action, due to elevated PTH levels that increase renal phosphate excretion. However, mice with hypophosphatemia secondary to ablation of the renal sodium-dependent phosphate transport protein 2a (Npt2a), have not been reported to develop rickets. Because activation of the mitochondrial apoptotic pathway by phosphate is required for hypertrophic chondrocyte apoptosis in vivo, investigations were undertaken to address this paradox. Analyses of the Npt2a null growth plate demonstrate expansion of the hypertrophic chondrocyte layer at 2 wk of age, with resolution of this abnormality by 5 wk of age. This is temporally associated with an increase in circulating levels of 1,25-dihydroxyvitamin D. To address whether the receptor-dependent actions of this steroid hormone are required for normalization of the growth plate phenotype, the Npt2a null mice were mated with mice lacking the vitamin D receptor or were rendered vitamin D deficient. These studies demonstrate that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for maintenance of a normal growth plate phenotype in the Npt2a null mice.

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