Clinical Potential of Targeting Fibroblast Growth Factor‐23 and αKlotho in the Treatment of Uremic Cardiomyopathy

Law, Jonathan P; Price, Anna; Pickup, Luke; Radhakrishnan, Ashwin; Weston, Chris J.; Jones, Alan M.; McGettrick, Helen M.; Chua, Winnie; Steeds, Richard P.; Fabritz, Larissa; Kirchhof, Paulus; Pavlović, Davor; Townend, Jonathan; Ferro, Charles J.

doi:10.1161/jaha.120.016041

Cited by 25 publications

(18 citation statements)

References 198 publications

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“…MR was not associated with myocardial α-Klotho mRNA expression. A decrease in renal and circulating α-Klotho is typical for hypertension and CKD [ 34 , 38 , 39 , 40 ], including the models used here. Thus, a decline in α-Klotho kidney production and circulating α-Klotho may be an additional factor in the progression of MR.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of MR in CKD are poorly understood and may include hemodynamic and non-hemodynamic factors [ 26 , 27 , 28 , 29 , 30 , 31 ]. The increased production of fibroblast growth factor-23 [ 32 , 33 ], αKlotho [ 34 , 35 ], and calcitriol [ 36 ] deficiencies are major candidate non-hemodynamic factors of cardiomyopathy progression in patients with CKD [ 37 , 38 , 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy

Bogdanova¹,

Beresneva²,

Galkina³

et al. 2021

IJMS

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Background: Arterial hypertension (AH) is associated with heart and chronic kidney disease (CKD). However, the precise mechanisms of myocardial remodeling (MR) in the settings of CKD remain elusive. We hypothesized that TRPC6, calcineurin/NFAT, and Wnt/β-catenin signaling pathways are involved in the development of MR in the background of CKD and AH. Methods: Early CKD was induced by performing a 5/6 nephrectomy (5/6NE) in spontaneously hypertensive rats (SHR-NE). Sham-operated (SO) SHR (SHR-SO) and Wistar Kyoto (WKY-SO) rats served as controls. Systolic blood pressure (SBP), heart rate, myocardial mass index (MMI), serum creatinine, cardiomyocyte diameter (dCM), myocardial fibrosis (MF), serum and kidney α-Klotho levels, myocardial expression of calcineurin (CaN), TRPC6, and β-catenin were measured two months after 5/6NE or SO. Results: NE-induced kidney dysfunction corresponded to mild-to-moderate human CKD and was associated with an increase in FGF23 and a decrease in renal α-Klotho. The levels of SBP, MMI, dCM, and MF were higher in SHRs compared to WKY-SO as well as in SHR-NE vs. SHR-SO. The MR was associated with increased cardiomyocyte expression of CaN/NFAT and β-catenin along with its intracellular re-distribution. TRPC6 protein levels were substantially elevated in both SHR groups with higher Trpc6 mRNA expression in SHR-NE. Conclusions: The Wnt/β-catenin and TRPC6/CaN/NFAT hypertrophic signaling pathways seem to be involved in myocardial remodeling in the settings of AH and CKD and might be mediated by FGF23 and α-Klotho axis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy

Bogdanova¹,

Beresneva²,

Galkina³

et al. 2021

IJMS

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“…In our present study, we found that FGF-23 protein expression in heart tissue in CKD mice was similar to that in sham mice, suggesting that the high circulatory FGF-23 in CKD does not cause accumulation of FGF-23 in the heart. FGF-23 activates promoting cardiac hypertrophy gene transcription by binding to FGF receptors (FGFRs) on the surface of cardiomyocytes membrane, instead of directly entering the cells ( 41 ). Therefore, the function and activity of the FGFRs may be more important.…”

Section: Discussionmentioning

confidence: 99%

Uraemic Cardiomyopathy in Different Mouse Models

Chen

Xie

et al. 2021

Front. Med.

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Uraemic cardiomyopathy (UCM) is one of the most common complications in chronic kidney disease (CKD). Our aim was to compare characteristics of various UCM mouse models. Mice were assigned to the following groups: the pole ligation group, 5/6 nephrectomy group (5/6Nx), uninephrectomy plus contralateral ischemia followed by reperfusion group (IR), adenine group, and sham group. Mice were sacrificed at 4, 8, and 16 weeks after surgery in the pole ligation, 5/6Nx, and IR groups, respectively. In the adenine group, mice were sacrificed at 16 weeks after the adenine diet. The structure and function of the heart and the expression of fibroblast growth factor 23 (FGF-23) and growth differentiation factor 15 (GDF-15) in hearts were assessed. The mortality in the 5/6 Nx group was significantly higher than that in the pole ligation, IR, and adenine groups. Echocardiogram and histological examination showed cardiac hypertrophy in the adenine,5/6Nx, ligation group, and IR group. In addition, cardiac fibrosis occurred in all CKD modeling groups. Interestingly, cardiac fibrosis was more serious in the IR and adenine groups. FGF-23 expression in sham mice was similar to that in modeling groups; however, the GDF-15 level was decreased in modeling groups. Our results suggest that the four models of UCM show different phenotypical features, molding time and mortality. GDF-15 expression in the hearts of UCM mice was downregulated compared with sham group mice.

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“…However, this mechanism has been suggested to be independent from alpha-Klotho, which is a co-receptor for FGF23-mediated regulation of mineral metabolism [ 33 ]. The failing heart can also be a major source of circulating FGF23, and patients who experience recurrent AF 6 months after AF ablation were observed to have greater left atrial FGF23 levels and lower soluble Klotho than patients with normal renal function [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study

et al. 2021

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Background Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. Methods and findings For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. Conclusions Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. Trial registration Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom

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Clinical Potential of Targeting Fibroblast Growth Factor‐23 and αKlotho in the Treatment of Uremic Cardiomyopathy

Cited by 25 publications

References 198 publications

Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy

Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy

Uraemic Cardiomyopathy in Different Mouse Models

Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study

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