Calcium (Ca(2+)) and phosphate (PO(4)(3-)) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and ...reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca(2+) levels by increasing Ca(2+) reabsorption and 1,25-dihydroxyvitamin D 1,25(OH)(2)D production by the kidney, enhancing Ca(2+) and PO(4)(3-) intestinal absorption and increasing Ca(2+) and PO(4)(3-) efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)(2)D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)(2)D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO(4)(3-) handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.
Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and ...iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1β (IL-1β) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1β injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1β injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3ko mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.
The planarity of the second stable conformer of 1,3‐butadiene, the archetypal diene for the Diels–Alder reaction in which a planar conjugated diene and a dienophile combine to form a ring, is not ...established. The most recent high level calculations predicted the species to adopt a twisted, gauche structure owing to steric interactions between the inner terminal hydrogens rather than a planar, cis structure favored by the conjugation of the double bonds. The structure cis‐1,3‐butadiene is unambiguously confirmed experimentally to indeed be gauche with a substantial dihedral angle of 34°, in excellent agreement with theory. Observation of two tunneling components indicates that the molecule undergoes facile interconversion between two equivalent enantiomeric forms. Comparison of experimentally determined structures for gauche‐ and trans‐butadiene provides an opportunity to examine the effects of conjugation and steric interactions.
Twist and shout: The structure of gauche‐butadiene has been determined using a combination of sensitive microwave experiments, unambiguously proving its non‐planarity with a twist angle of 34°. High‐level theoretical calculations show that the cis structure is a transition state between the two gauche minima on the potential energy surface (see picture).
Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic ...targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.
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•In the absence of α-klotho, FGF23 induces binding of FGFR4 to PLCγ•FGF23 activates calcineurin/NFAT signaling in cardiac myocytes via FGFR4•FGFR4 blockade protects CKD rats with high serum FGF23 from cardiac hypertrophy•Knockin mice carrying a FGFR4 gain-of-function mutation develop cardiac hypertrophy
Grabner et al. reveal that FGFR4 mediates the pro-hypertrophic cardiac effects of FGF23, a phosphate-regulating hormone elevated in patients with chronic kidney disease (CKD). Activation of FGFR4/calcineurin/NFAT signaling is sufficient to induce cardiac hypertrophy in mice, while FGFR4 blockade attenuates cardiac hypertrophy in a rat model of CKD.
Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD ...progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.
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Calcium has recently been shown to regulate fibroblast growth factor 23 (FGF-23), a bone-derived phosphate and vitamin D-regulating hormone. To better understand the regulation of FGF-23 by calcium, ...phosphorus, 1,25 dihydroxyvitamin D3 1,25(OH)2D, and PTH, we examined FGF-23 expression under basal conditions and in response to PTH, doxercalciferol, or high-calcium diet treatment in Gcm2−/− and Cyp27b1−/− mutant mice. Gcm2−/− mice exhibited low serum PTH and 1,25(OH)2D concentrations, hypocalcemia, and hyperphosphatemia, whereas Cyp27b1−/− mice had high PTH, undetectable 1,25(OH)2D, hypocalcemia, and hypophosphatemia. Serum FGF-23 levels were decreased in both mutant models. Doxercalciferol administration increased serum FGF-23 levels in both mutant models. PTH administration to Gcm2−/− mice also increased serum FGF-23 levels, in association with an increase in both 1,25(OH)2D and calcium concentrations. Multiple regression analysis of pooled data indicated that changes in FGF-23 were positively correlated with serum calcium and 1,25(OH)2D but not related to changes in serum phosphate concentrations. A high-calcium diet also increased serum FGF-23 concentrations in Cyp27b1−/− mice in the absence of 1,25(OH)2D and in Gcm2−/− mice with low PTH. The addition of calcium to the culture media also stimulated FGF-23 message expression in MC3T3-E1 osteoblasts. In addition, FGF-23 promoter activity in cultured osteoblasts was inhibited by the L-calcium-channel inhibitor nifedipine and stimulated by calcium ionophores. The effects of chronic low calcium to prevent 1,25(OH)2D and PTH stimulation of FGF-23 in these mutant mouse models suggest that suppression of FGF-23 plays an important physiological adaptive response to hypocalcemia.
Rotational spectroscopy is an invaluable tool to unambiguously determine the molecular structure of a species, and sometimes even to establish its very existence. This article illustrates how ...experimental and theoretical state‐of‐the‐art tools can be used in tandem to investigate the rotational structure of molecules, with particular emphasis on those that have long remained elusive. The examples of three emblematic species—gauche‐butadiene, disilicon carbide, and germanium dicarbide—highlight the close, mutually beneficial interaction between high‐level theoretical calculations and sensitive microwave measurements. Prospects to detect other elusive molecules of chemical and astronomical interest are discussed.
Hunting elusive species: Close coordination of theoretical calculations and rotational spectroscopy can be used efficiently to detect and structurally characterize several elusive species, as gauche‐butadiene, SiCSi, and GeC2, three emblematic species for which the experimental observation was only made possible by this close interaction (see picture).
Abstract
We present a robust approach to generate a continuously tunable, low phase noise, Hz linewidth and mHz/s stability THz emission in the 0.1 THz to 1.4 THz range. This is achieved by ...photomixing two commercial telecom, distributed feedback lasers locked by optical-feedback onto a single highly stable V-shaped optical cavity. The phase noise is evaluated up to 1.2 THz, demonstrating Hz-level linewidth. To illustrate the spectral performances and agility of the source, low pressure absorption lines of methanol and water vapors have been recorded up to 1.4 THz. In addition, the hyperfine structure of a water line at 556.9 GHz, obtained by saturation spectroscopy, is also reported, resolving spectral features displaying a full-width at half-maximum of 10 kHz. The present results unambiguously establish the performances of this source for ultra-high resolution molecular physics.
Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify ...gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/α-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3(-/-)) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that α-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases.
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