A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

Bao, Jing-Fu; Hu, Panpan; She, Qin-Ying; Li, Aiqing

doi:10.1681/asn.2020010081

Cited by 17 publications

(11 citation statements)

References 127 publications

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“…Later, CKD-MBD was considered a cardiovascular risk factor, and vitamin D and FGF-23 have gained wide concern ( 26 ) (Cluster ID #5, ID #7, and ID #19, Figure 5A ), especially FGF-23 was found to correlate to LVH and can directly induce LVH ( 12 , 27 ). In recent years, the hotspot of uremic cardiomyopathy was on “klotho” (Cluster ID #3, Figure 5A ), which declines CKD and has FGF-23-dependent and FGF-23-independent protective effects on the myocardium ( 28 ).…”

Section: Resultsmentioning

confidence: 99%

“…Most recent progress on uremic cardiomyopathy is mainly based on studies performed by Hu et al ( 29 ) and Leifheit-Nestler et al ( 30 ), who found that soluble klotho can alleviate LVH in CKD. Further investigations found the protective effects of soluble klotho are FGF-23-dependent and FGF-23-independent ( 28 ), thus, implying another therapeutic strategy for uremic cardiomyopathy ( Figures 5A , 7 ).…”

Section: Discussionmentioning

confidence: 99%

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A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021

Bao

She

et al. 2022

Front. Cardiovasc. Med.

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BackgroundUremic cardiomyopathy is commonly presented in chronic kidney disease (CKD), and it severely affects the prognosis of patients with CKD. In the past few decades, the investigation of uremic cardiomyopathy has developed rapidly. However, no report has summarized the situation of uremic cardiomyopathy research to date. This study aimed to evaluate the state of uremic cardiomyopathy research in the last 30 years and identify important topics and achievements, as well as emerging trends through bibliometric analysis.Materials and MethodsPublications related to uremic cardiomyopathy were collected from Science Citation Index Expanded. HistCite, VOSviewer, CiteSpace, and the Bibliometrix Package were used for bibliometric analysis and visualization, including the analysis of the overall distribution of the annual publication, leading countries, and active institutions and authors, core journals, co-cited references, and keywords.ResultsA total of 2,403 studies related to uremic cardiomyopathy were obtained, and progress related to uremic cardiomyopathy was slower in past 3 years. A total of 10,077 authors from 2,697 institutions in 89 countries or regions reported investigations on uremic cardiomyopathy. The United States of America was the most productive and the most cited country. Myles Wolf, Joseph I Shapiro, and Carmine Zoccali published most articles in uremic cardiomyopathy, and journals in nephrology possessed core status in the field. Phosphate metabolism was the hotspot in uremic cardiomyopathy research in recent years, and future progress may concentrate on phosphate metabolism, endogenous natriuretic factors, and novel biomarkers.ConclusionThe United States of America and European countries played central roles in uremic cardiomyopathy research, while Chinese scholars should be more involved in this field. Global publications on uremic cardiomyopathy have entered platform stage, and the fibroblast growth factor-23-klotho axis remained a hotspot in this field. Endogenous natriuretic factors and novel biomarkers may be potential directions in future investigations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021

Bao

She

et al. 2022

Front. Cardiovasc. Med.

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“…High FGF23 in plasma has been linked to a higher risk of cardiovascular disease, all‐cause mortality, infection, and inflammation 4 . Although the direct effect of FGF23 is still under debate, at least for cardiac hypertrophy, the fact is that high FGF23 levels are observed under stress states 1,5 . In addition to calcitriol and PTH, calcium, iron, inflammatory factors, hypoxia, erythropoietin (EPO), extracellular volume, and leptin have recently emerged as regulators of FGF23 1,6 …”

Section: Introductionmentioning

confidence: 99%

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage

et al. 2021

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Fibroblast growth factor 23 (FGF23) is a main regulator of mineral homeostasis. Low and high circulating FGF23 levels are associated with bone, renal, cardiovascular diseases, and increased mortality. Understanding the factors and signaling pathways affecting FGF23 levels is crucial for the management of these diseases and their complications. Here, we show that activation of the Jak1/Stat3 signaling pathway leads to inflammation in liver and to an increase in hepatic FGF23 synthesis, a key hormone in mineral metabolism. This increased synthesis leads to massive C‐terminal FGF23 circulating levels, the inactive C‐terminal fragment, and increased intact FGF23 levels, the active form, resulting in imbalanced production and cleavage. Liver inflammation does not lead to activation of the calcineurin‐NFAT pathway, and no signs of systemic inflammation could be observed. Despite the increase of active intact FGF23, excessive C‐terminal FGF23 levels block the phosphaturic activity of FGF23. Therefore, kidney function and renal αKlotho expression are normal and no activation of the MAPK pathway was detected. In addition, activation of the Jak1/Stat3 signaling pathway leads to high calcitriol levels and low parathyroid hormone production. Thus, JAK1 is a central regulator of mineral homeostasis. Moreover, this study also shows that in order to assess the impact of high FGF23 levels on disease and kidney function, the source and the balance in FGF23 production and cleavage are critical.

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“…Fibroblast growth factor 23 is considered to be a major contributor to the development of LVH, heart failure, atrial fibrillation, and increased cardiovascular and all-cause mortality in CKD (Faul et al, 2011;Kendrick et al, 2011;Scialla et al, 2014;Mehta et al, 2016) and non-CKD (Ix et al, 2012;Kestenbaum et al, 2014;Lutsey et al, 2014) populations. However, it is still intensively discussed whether elevated FGF23 is cardiotoxic per se (Marthi et al, 2018;Pastor-Arroyo et al, 2018;Zhou et al, 2018;Bao et al, 2020). All previously reported animal models developing LVH in the presence of elevated circulating Fgf23 levels due to experimental uremia, genetic deletion of klotho, high phosphate diet, or injection of recombinant FGF23 protein display a variety of systemic changes that are all proven contributors to cardiac injury, making it difficult to elucidate the causative role of FGF23 for LVH in these studies (Faul et al, 2011;Andrukhova et al, 2014;Grabner et al, 2015; Yang et al, 2015;Leifheit-Nestler et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice

Leifheit-Nestler

Wagner

Richter

et al. 2021

Front. Cell Dev. Biol.

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Fibroblast growth factor (FGF) 23 is elevated in chronic kidney disease (CKD) to maintain phosphate homeostasis. FGF23 is associated with left ventricular hypertrophy (LVH) in CKD and induces LVH via klotho-independent FGFR4-mediated activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling in animal models, displaying systemic alterations possibly contributing to heart injury. Whether elevated FGF23 per se causes LVH in healthy animals is unknown. By generating a mouse model with high intra-cardiac Fgf23 synthesis using an adeno-associated virus (AAV) expressing murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promoter, we investigated how cardiac Fgf23 affects cardiac remodeling and function in C57BL/6 wild-type mice. We report that AAV-Fgf23 mice showed increased cardiac-specific Fgf23 mRNA expression and synthesis of full-length intact Fgf23 (iFgf23) protein. Circulating total and iFgf23 levels were significantly elevated in AAV-Fgf23 mice compared to controls with no difference in bone Fgf23 expression, suggesting a cardiac origin. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of neonatal rat ventricular myocytes (NRVM) and induced pro-hypertrophic NFAT target genes in klotho-free culture conditions in vitro. Further analysis revealed that renal Fgfr1/klotho/extracellular signal-regulated kinases 1/2 signaling was activated in AAV-Fgf23 mice, resulting in downregulation of sodium-phosphate cotransporter NaPi2a and NaPi2c and suppression of Cyp27b1, further supporting the bioactivity of cardiac-derived iFgf23. Of interest, no LVH, LV fibrosis, or impaired cardiac function was observed in klotho sufficient AAV-Fgf23 mice. Verified in NRVM, we show that co-stimulation with soluble klotho prevented Fgf23-induced cellular hypertrophy, supporting the hypothesis that high cardiac Fgf23 does not act cardiotoxic in the presence of its physiological cofactor klotho. In conclusion, chronic exposure to elevated cardiac iFgf23 does not induce LVH in healthy mice, suggesting that Fgf23 excess per se does not tackle the heart.

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A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

Cited by 17 publications

References 127 publications

A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021

A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021

Systemic Jak1 activation provokes hepatic inflammation and imbalanced FGF23 production and cleavage

Cardiac Fibroblast Growth Factor 23 Excess Does Not Induce Left Ventricular Hypertrophy in Healthy Mice

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