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Browsing by Subject "Phosphate metabolism"
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Item Effect of kidney donation on bone mineral metabolism(Public Library of Science, 2020-07-07) Hiemstra, Thomas F.; Smith, Jane C.; Lim, Kenneth; Xu, Dihua; Kulkarni, Shreya; Bradley, J. Andrew; Paapstel, Kaido; Schoenmakers, Inez; Bradley, John R.; Tomlinson, Laurie; McEniery, Carmel M.; Wilkinson, Ian B.; Medicine, School of MedicineKidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9–1.2) to 1.3(1.1–1.4) mmol/L, p <0.001) but declined to 0.8(0.8–1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.Item Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease(Elsevier, 2022) Yanucil, Christopher; Kentrup, Dominik; Campos, Isaac; Czaya, Brian; Heitman, Kylie; Westbrook, David; Osis, Gunars; Grabner, Alexander; Wende, Adam R.; Vallejo, Julian; Wacker, Michael J.; Navarro-Garcia, Jose Alberto; Ruiz-Hurtado, Gema; Zhang, Fuming; Song, Yuefan; Linhardt, Robert J.; White, Kenneth; Kapiloff, Michael S.; Faul, Christian; Medical and Molecular Genetics, School of MedicineFibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that is elevated in patients with chronic kidney disease and associated with cardiovascular mortality. Experimental studies showed that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed that the complex of FGF23 and FGFR1, the physiologic FGF23 receptor in the kidney, includes soluble α-klotho (klotho) and heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether soluble klotho, a circulating protein with cardio-protective properties, and heparin, a factor that is routinely infused into patients with kidney failure during the hemodialysis procedure, regulate FGF23/FGFR4 signaling and effects in cardiac myocytes. We developed a plate-based binding assay to quantify affinities of specific FGF23/FGFR interactions, and found that soluble klotho and heparin mediate FGF23 binding to distinct FGFR isoforms. Heparin specifically mediated FGF23 binding to FGFR4, and increased FGF23 stimulatory effects on hypertrophic growth and contractility in isolated cardiac myocytes. When repetitively injected into two different mouse models with elevated serum FGF23 levels, heparin aggravated cardiac hypertrophy. We also developed a novel procedure for the synthesis and purification of recombinant soluble klotho, which showed anti-hypertrophic effects in FGF23-treated cardiac myocytes. Thus, soluble klotho and heparin act as independent FGF23 coreceptors with opposite effects on the pathologic actions of FGF23, with soluble klotho reducing and heparin increasing FGF23-induced cardiac hypertrophy. Hence, whether heparin injections during hemodialysis in patients with extremely high serum FGF23 levels contribute to their high rates of cardiovascular events and mortality remains to be studied.Item Testing bone cell models responsive to a soluble form of klotho(2016-11) Bonfitto, Anna; White, Kenneth E.Fibroblast growth factor-23 (FGF23) is a hormone produced in bone that acts upon the kidney to control blood phosphate and 1,25-(OH)2 vitamin D concentrations. Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major public health problem, affecting 1 in 8 individuals. These patients can have markedly elevated FGF23 at end stage disease which is associated with metabolic bone anomalies, left ventricular hypertrophy, as well as increased mortality (>6-fold). The FGF23 co-receptor αKlotho (αKL) is a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as a cleavage product of mKL (‘cleaved’, or cKL). Previously, a patient with increased plasma cKL from a balanced translocation between chromosomes 9 and 13 in the KLOTHO gene presented with metabolic bone disease and a complex endocrine profile, despite hypophosphatemia. The lack of a reliable cell model in which to study potential FGF23-cKL interactions is a major hurdle for the field of phosphate metabolism. The goal of the present studies was to test and characterize bone cell lines that may respond to FGF23 and/or cKL, permitting study of novel aspects of phosphate handling and control of FGF23 expression. It was confirmed that stable delivery of cKL via AAV2/8 to wild type (WT) and KL-KO mice resulted in highly elevated bone FGF23 mRNA. MC3T3 (mouse) and ROS (rat) osteoblastic cell lines were tested for p-ERK1/2 responses to control FGFs, as well as FGF23 and cKL, alone or in combination. Importantly, both cell lines demonstrated responsiveness to FGF23+cKL only, and not the individual factors. To test responsiveness at the cell level, EGR1 mRNA was tested as an index of FGFR activity and showed modest increases with the same treatments, supporting that other factors may be required for full transcriptional effects. The present studies show that MC3T3 have FGF-dependent signaling capabilities, and that the combination of FGF23+cKL is required for efficient MAPK signaling. These results demonstrated that cKL provision is permissive for efficient FGF23 signaling in bone, and revealed important implications for the regulation of FGF23 and cKL in Mendelian, and common, genetic disorders of phosphate handling and biomineralization.