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Vitamin D-unabhängige Funktion von Fgf23 und Klotho

Abstract
Fibroblast growth factor-23 (FGF23) is a hormone secreted from osteoblasts and osteocytes in response to elevated extracellular phosphate and vitamin D. Binding of FGF23 to FGF receptors on target cells requires the co-receptor Klotho. FGF23 downregulates renal proximal tubular reabsorption of phosphate, and inhibits renal synthesis of the vitamin D hormone through suppression of the renal 1a-hydroxlase. The exact mechanism by which FGF23 suppresses proximal tubular membrane expression of sodium-phosphate cotransporters is not known. In addition, the physiological role of the putative suppressive effect of FGF23 on parathyroid hormone secretion is currently unclear, and it has always been an enigma why FGF23 does not lower serum calcium despite suppression of vitamin D hormone synthesis. Klotho and Fgf23 knockout mice are characterized by severe hypervitaminosis D due to loss of the suppressive effect on renal 1a-hydroxlase. Therefore, the intricate association between Fgf23/Klotho signaling and vitamin D metabolism has made it difficult to clearly dissect the vitamin D independent functions of Fgf23 and Klotho in vivo. Preliminary data from 9-month-old Fgf23/vitamin D receptor (VDR) compound mutants on a rescue diet enriched with calcium, phosphorus, and lactose revealed renal calcium and sodium wasting, hyperphosphatemia, and severe secondary hyperparathyroidism in Fgf23/VDR compound mutants. Further experiments suggested that lack of Fgf23 signaling through Fgf23 or Klotho deficiency reduced distal renal tubular transport of the fully glycosylated transient receptor potential vanilloid-5 (TRPV5) channel to the plasma membrane by a mechanism involving with-no-lysine kinase-4 (WNK4) and serum- and glucocorticoid-inducible kinase-1 (SGK1) in a vitamin D independent fashion. These data suggest that Fgf23 is not only a phosphaturic but also a calcium-conserving hormone, and suggest crosstalk of Fgf23 and aldosterone signaling at the level of SGK1, establishing a novel molecular link between phosphate, calcium, and sodium homeostasis.The central aim of the current proposal is to elucidate further the vitamin D independent molecular functions of Fgf23 and Klotho in the regulation of renal calcium, phosphate, and sodium reabsorption, in the regulation of PTH secretion, and in disease progression of experimental chronic kidney disease (CKD). Our hypothesis is that Fgf23 signaling directly regulates distal tubular calcium and sodium reabsorption as well as proximal tubular phosphate reabsorption through the ERK1/2-SGK1 signaling pathway, and that Fgf23 deficiency partially protects against progression of CKD. To test this hypothesis, we propose in vivo gain-of-function experiments with recombinant FGF23 and acute loss-of-function experiments with anti-FGF23 antibodies in wild-type, VDR, Fgf23/VDR, and Klotho/VDR mutant mice, as well as in vitro experiments using isolated proximal and distal tubular segments, cultured primary proximal and distal tubular cells, and cultured primary parathyroid cells from wild-type, Fgf23, Klotho, VDR, Fgf23/VDR, and Klotho/VDR mutants. The proposed experiments will significantly advance our knowledge about the molecular role of Fgf23 and Klotho in calcium, phosphate, and sodium homeostasis, as well as in the progression of CKD. Thus, the proposed work may have important implications for human and veterinary clinical medicine.
Statistik Austria science classification
403024         Veterinary pathology
403026         Veterinary physiology
Lemma
Vit D-unabhängige Funktion
Project leader
Erben Reinhold
Duration
01.11.11-31.10.16
Programme
FWF Einzelprojekte
Type of Research
Basic research
Vetmed Research Units
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology, Pathophysiology, and Experimental Endocrinology
Funded by
FWF - Fonds zur Förderung der wissenschaftlichen Forschung, Sensengasse 1, 1090 Wien, Austria

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15 Publications

Radloff, J; Pagitz, M; Andrukhova, O; Oberbauer, R; Burgener, IA; Erben, RG (2021): Aldosterone Is Positively Associated With Circulating FGF23 Levels in Chronic Kidney Disease Across Four Species, and May Drive FGF23 Secretion Directly. Front Physiol. 2021; 12:649921
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Erben, RG; (2018): Fibroblast growth factor-23. IN: Choi, S [Hrsg.]: Encyclopedia of Signaling Molecules. 2. Ed. New York, Springer, pp. 1-10. ISBN: 978-1-4614-6438-9.

Andrukhova, O; Schüler, C; Bergow, C; Petric, A; Erben, RG (2018): Augmented Fibroblast Growth Factor-23 Secretion in Bone Locally Contributes to Impaired Bone Mineralization in Chronic Kidney Disease in Mice. Front Endocrinol (Lausanne). 2018; 9:311
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Erben, RG (2018): Physiological Actions of Fibroblast Growth Factor-23. Front Endocrinol (Lausanne). 2018; 9:267
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Erben, RG (2018): α-Klotho"s effects on mineral homeostasis are fibroblast growth factor-23 dependent. Curr Opin Nephrol Hypertens. 2018; 27(4):229-235
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Erben, RG (2017): Pleiotropic Actions of FGF23. Toxicol Pathol. 2017; 45(7):904-910
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Andrukhova, O; Bayer, J; Schüler, C; Zeitz, U; Murali, SK; Ada, S; Alvarez-Pez, JM; Smorodchenko, A; Erben, RG (2017): Klotho Lacks an FGF23-Independent Role in Mineral Homeostasis. J Bone Miner Res. 2017; 32(10):2049-2061

Erben, RG; Andrukhova, O (2017): FGF23-Klotho signaling axis in the kidney. Bone. 2017; 100:62-68
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Andrukhova, O; Streicher, C; Zeitz, U; Erben, RG (2016): Fgf23 and parathyroid hormone signaling interact in kidney and bone. Mol Cell Endocrinol. 2016; 436:224-239
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Erben, RG (2016): Update on FGF23 and Klotho signaling. Mol Cell Endocrinol. 2016; 432:56-65
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Murali, SK; Andrukhova, O; Clinkenbeard, EL; White, KE; Erben, RG (2016): Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice. PLoS Biol. 2016; 14(4):e1002427
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Murali, SK; Roschger, P; Zeitz, U; Klaushofer, K; Andrukhova, O; Erben, RG (2016): FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. J Bone Miner Res. 2016; 31(1):129-142

Erben, RG (2015): Hypothesis: Coupling between Resorption and Formation in Cancellous bone Remodeling is a Mechanically Controlled Event. Front Endocrinol (Lausanne). 2015; 6:82
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Andrukhova, O; Smorodchenko, A; Egerbacher, M; Streicher, C; Zeitz, U; Goetz, R; Shalhoub, V; Mohammadi, M; Pohl, EE; Lanske, B; Erben, RG (2014): FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J. 2014; 33(3):229-246
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Andrukhova, O; Zeitz, U; Goetz, R; Mohammadi, M; Lanske, B; Erben, RG (2012): FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS), Stockholm, SWEDEN, Sweden, MAY 19-23, 2012. Bone. 2012; 51(3):621-628
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