Dataset Information

Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

ABSTRACT: Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. ?-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klotho-mediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation via Klotho-independent FGFR4 activation.FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients, and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model.Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in interleukin-1? release via Klotho-independent FGFR4-mediated activation of phospholipase C?/nuclear factor of activated T-cells signalling. In addition, Klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of Klotho led to an attenuation of airway inflammation.Cigarette smoke induces airway inflammation by downregulation of Klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD.

SUBMITTER: Krick S

PROVIDER: S-EPMC6044452 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

Krick Stefanie S Grabner Alexander A Baumlin Nathalie N Yanucil Christopher C Helton Scott S Grosche Astrid A Sailland Juliette J Geraghty Patrick P Viera Liliana L Russell Derek W DW Wells J Michael JM Xu Xin X Gaggar Amit A Barnes Jarrod J King Gwendalyn D GD Campos Michael M Faul Christian C Salathe Matthias M

The European respiratory journal 20180704 1

Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klotho-mediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation <i>via</i> Klotho-independent FGFR4 activation.F ...[more]

PMID: 29748308

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Project description:Rationale & Objective Patients with chronic kidney failure have markedly elevated fibroblast growth factor 23 (FGF-23) levels and decreased soluble Klotho levels. However, no studies have examined the effects of hemodialysis initiation on the levels of these hormones and other parameters of mineral metabolism. Study Design Prospective single-arm study. Setting & Participants 20 individuals with incident kidney failure initiating hemodialysis. Exposure Initiation of hemodialysis. Dose adjustments of phosphate binders and vitamin D receptor activators and use of calcimimetics, erythropoiesis-stimulating agents, and intravenous iron were prohibited. Outcomes Changes in serum levels of FGF-23, soluble Klotho, and other biochemical parameters of mineral metabolism, measured before and after each hemodialysis session, for a total of 4 sessions over 5 days. Analytical Approach Repeated-measures analysis of variance. Results At baseline, participants had 18-fold higher median FGF-23 levels and 1.6-fold lower mean soluble Klotho levels compared with age- and sex-matched healthy individuals. Initiation of hemodialysis led to progressive reductions in serum phosphorus, intact parathyroid hormone, and FGF-23 levels, with dialysis-related fluctuations. No reductions were observed in levels of ?1-microglobulin, which has molecular weight comparable to FGF-23. The magnitude of the FGF-23 level reductions was strongly associated with concomitant changes in serum phosphorus levels but not with the changes in intact parathyroid hormone levels. Soluble Klotho levels did not change after the initiation of hemodialysis. Limitations Single-arm design, small sample size, short follow-up period. Conclusions Initiation of hemodialysis in patients with chronic kidney failure led to progressive reductions in FGF-23 levels in association with reductions in serum phosphorus levels. These results suggest that phosphorus is a strong inducer of FGF-23 production and that regulation of FGF-23 production is a rapid process.

Project description:BACKGROUND AND OBJECTIVES:Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and ?-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS:Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, ?-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS:In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or ?-klotho levels.

Project description:AimsKlotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition.Methods and resultsA total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; Pinteraction < 0.01).ConclusionsLow Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.

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Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

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Fibroblast growth factor 23 and Klotho contribute to airway inflammation.

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