FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway

Andrukhova, Olena; Zeitz, Ute; Goetz, Regina; Mohammadi, Moosa; Lanske, Beate; Erben, Reinhold G.

doi:10.1016/j.bone.2012.05.015

Cited by 191 publications

(159 citation statements)

References 27 publications

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“…A recent study showed that FGF-23 directly downregulates membrane expression of the renal NaPi2a (SLC34A1). 25 Reduction of FGF-23 and concomitant reduction of the renal phosphate fractional excretion have previously been observed in clinical studies in patients with CKD treated with P binders. 26,27 The reduced P intestinal intake mechanism posited for tenapanor is supported by the robust attenuation of ectopic deposition of Ca and phosphate (presumably as hydroxyapatite) in the aortic arch and stomach in tenapanor-treated rats (Figure 8).…”

Section: Discussionmentioning

confidence: 81%

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Labonté

Carreras

Leadbetter

et al. 2015

Journal of the American Society of Nephrology

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In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodiumhydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [ 33 P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.

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Section: Discussionmentioning

confidence: 81%

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Labonté

Carreras

Leadbetter

et al. 2015

Journal of the American Society of Nephrology

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“…Although this may seem to be counterintuitive, it is important to note that the activity of the ERK pathway is tissue and cell type dependent (38). The ERK pathway regulates a wide array of physiologic and pathologic processes, including proliferation, development, and metabolism, and while in the kidneys, as a downstream effector of FGF23 signaling, it participates in regulating phosphorus homeostasis (39), in cancer cells it enhances proliferation as a downstream effector of multiple growth factors, including IGF-1 (40). Furthermore, the effect of klotho on various Only KL1 domain suppresses IGF-1 signaling and interacts with the IGF-1R in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Ligumsky

Rubinek

Merenbakh-Lamin

et al. 2015

Molecular Cancer Research

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Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities.Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer.

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“…NHERF1 assembles a ternary complex with NPT2A and ezrin, thereby linking the transporter to the actin cytoskeleton. NHERF1 is essential for the inhibitory action of PTH and FGF23 on phosphate transport (12,17,20). NHERF1-null mice and humans harboring mutations in SLC9A3R1 exhibit pronounced phosphate wasting, nephrolithiasis, and skeletal dis-* This work was supported by National Institutes of Health Grants DK069998 and DK105811 (to P. A. F.), DK101484 and DK100357 (to O.…”

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confidence: 99%

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport

Sneddon¹,

Ruiz

Gallo

et al. 2016

Journal of Biological Chemistry

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Parathyroid hormone (PTH) and FGF23 are the primary hormones regulating acute phosphate homeostasis. Human renal proximal tubule cells (RPTECs) were used to characterize the mechanism and signaling pathways of PTH and FGF23 on phosphate transport and the role of the PDZ protein NHERF1 in mediating PTH and FGF23 effects. RPTECs express the NPT2A phosphate transporter, ␣Klotho, FGFR1, FGFR3, FGFR4, and the PTH receptor. FGFR1 isoforms are formed from alternate splicing of exon 3 and of exon 8 or 9 in Ir-like loop 3. Exon 3 was absent, but mRNA containing both exons 8 and 9 is present in cytoplasm. Using an FGFR1c-specific antibody together with mass spectrometry analysis, we show that RPTECs express FGFR-␤1C. The data are consistent with regulated FGFR1 splicing involving a novel cytoplasmic mechanism. PTH and FGF23 inhibited phosphate transport in a concentration-dependent manner. At maximally effective concentrations, PTH and FGF23 equivalently decreased phosphate uptake and were not additive, suggesting a shared mechanism of action. Protein kinase A or C blockade prevented PTH but not FGF23 actions. Conversely, inhibiting SGK1, blocking FGFR dimerization, or knocking down Klotho expression disrupted FGF23 actions but did not interfere with PTH effects. C-terminal FGF23(180 -251) competitively and selectively blocked FGF23 action without disrupting PTH effects. However, both PTH and FGF23-sensitive phosphate transport were abolished by NHERF1 shRNA knockdown. Extended treatment with PTH or FGF23 down-regulated NPT2A without affecting NHERF1. We conclude that FGFR1c and PTHR signaling pathways converge on NHERF1 to inhibit PTH-and FGF23-sensitive phosphate transport and down-regulate NPT2A.Parathyroid hormone (PTH) 2 and FGF23 display two remarkable features: 1) PTH and FGF23 exhibit parallel inhibition of renal phosphate transport mediated by NPT2A (sodium-dependent phosphate transporter-2a) but opposing actions on 1,25(OH) 2 -vitamin D; 2) despite being structurally and functionally distinct classes of membrane-delimited receptors, PTH and FGF receptors activate kinases that obligatorily phosphorylate NHERF1 at conserved sites required for their phosphaturic action. Phosphorus is essential for growth and maintenance of the skeleton and for generating high energy phosphate compounds. Evolutionary adaptation in humans and other terrestrial vertebrates to phosphorus-rich diets involves cell and molecular mechanisms ensuring the efficient urinary elimination of excess inorganic phosphate. The renal proximal tubule is the primary site of phosphate homeostasis and hormone-dependent phosphate transport. The NPT2A sodium-dependent phosphate cotransporter (SLC34A1) in proximal tubules is regulated by PTH and FGF23 (1, 2). PTH and FGF23 reduce phosphate uptake by sequestering and down-regulating NPT2A, thereby enhancing urinary phosphate excretion (3, 4). PTH actions are mediated by its cognate G protein-coupled PTH receptor (PTHR) (5, 6). Both PKA and PKC have been implicated in PTH-dependent inhibition of NPT2A (7-12)....

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FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway

Cited by 191 publications

References 27 publications

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport

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