FGF23 and klotho at the intersection of kidney and cardiovascular disease

Edmonston, Daniel L.; Grabner, Alexander; Wolf, Myles

doi:10.1038/s41569-023-00903-0

Cited by 26 publications

(20 citation statements)

References 248 publications

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“…FGF23 rises early in CKD in response to subtle increases in serum phosphate concentrations and prevents or delays hyperphosphatemia by activating complexes of FGF23 receptors and transmembrane klotho co-receptors in proximal tubules that lead to urinary excretion of phosphate [12,13]. It is markedly elevated in hyperphosphatemic states such as advanced CKD where it is linked to adverse cardiovascular outcomes mediated by the cardiac receptor FGFR4 [13]. Klotho-independent FGF23/FGFR4 signaling activates nuclear factor of activated T-cells (NFAT)-dependent mechanisms that lead to LVH in human and animal models of CKD [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…It is markedly elevated in hyperphosphatemic states such as advanced CKD where it is linked to adverse cardiovascular outcomes mediated by the cardiac receptor FGFR4 [13]. Klotho-independent FGF23/FGFR4 signaling activates nuclear factor of activated T-cells (NFAT)-dependent mechanisms that lead to LVH in human and animal models of CKD [13,14]. Since LVH also predicts QTc interval prolongation, we hypothesized it might mediate an indirect effect between FGF23 and QTc prolongation in CKD [15].…”

Section: Discussionmentioning

confidence: 99%

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QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

Sikaneta,

Ho,

Bellasi

et al. 2024

Cardiorenal Med

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Introduction: QTc interval prolongation is increasingly frequent as CKD advances and predicts death in dialysis. However, predictors and mortality-risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH, and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD. Methods: Participants underwent protocolized baseline and semi-annual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over three years. Results: 2,254 participants (34.1% female; mean age 68.7 years; mean glomerular filtration rate 41.4 ml/min/m2) enrolled. Baseline LVH (left ventricular mass index >131 g/m2 (>100 g/m2 if female)) was present in 10.8% and prolonged QTc intervals (>=500 ms) in 1.5%. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p=0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p<0.001) and adjusted (hazard ratio 3.15 (1.38, 7.16, p=0.006)) mortality rates than those with QTc intervals <500 ms. Conclusions: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH, and with a tripling of mortality-risk in patients with predialysis CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

Sikaneta,

Ho,

Bellasi

et al. 2024

Cardiorenal Med

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“…We included 24 datasets in the RNA-Seq data analysis, three biological replicates in each group. List of eight experimental groups as follows: (1) Kl_FGF23_1h; (2) Kl_Ctrl_1h; (3) WT_FGF23_1h; (4) WT_Ctrl_1h; (5) Kl_FGF23_24h; (6) Kl_Ctrl_24h; (7) WT_FGF23_24h; (8) WT_Ctrl_24h.…”

Section: Competing Interestsmentioning

confidence: 99%

“…Physiological regulators like dietary phosphate, 1,25(OH) 2 D 3 and PTH stimulate FGF23 transiently within a narrow limit 6 . In contrast, CKD is linked to consistently high FGF23 levels 6 .…”

Section: Introductionmentioning

confidence: 99%

“…These direct actions of FGF23 contradict the recent functional and structural data that support the essential role of transmembrane or circulatory soluble-Klotho in FGF23 actions through FGFR1 and FGFR4 1,2 . Physiological regulators like dietary phosphate, 1,25(OH)2D3 and PTH stimulate FGF23 transiently within a narrow limit 6 . In contrast, CKD is linked to consistently high FGF23 levels 6 .…”

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confidence: 99%

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Identification of novel and distinct FGF23 signaling in a Klotho-dependent and -independent manner

Kopper,

Pastor,

Moe

et al. 2024

Preprint

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Fibroblast growth factor-23 (FGF23) is crucial for phosphate and vitamin D homeostasis. Moreover, FGF23 levels are very high in patients with chronic kidney disease (CKD) with unclear functions. Binding of FGF23 to its coreceptor Klotho is considered essential for its actions. However, recent data suggested that CKD-related high FGF23 levels may have Klotho-independent cardiotoxic and inflammatory effects but the underlying signaling mechanism are unclear. Here, we performed a comprehensive and unbiased transcriptomic profiling in HEK293 cells, comparing the effects of 0.5 nM FGF23 for 1 hour (low-transitory: ~physiological) and 10 nM FGF23 for 24 hours (high-prolonged: ~pathological), in the presence and absence of Klotho. We found that, at physiological concentration, FGF23 action requires Klotho and follows the canonical MAPK signaling. Conversely, at pathological high levels, FGF23 acts both in the presence and in the absence of Klotho. In the presence of Klotho, high FGF23 activates a plethora of transcripts including the inflammatory genes (e.g. TGFB1, GDF15, ANXA1 and TNFRSF9/12) known to be elevated in patients with CKD. Interestingly, in the absence of Klotho, high FGF23 levels does also regulate a small and unique set of genes related to post-transcriptional modifications and translation initiation. To conclude, Klotho is essential for FGF23 signaling at physiological FGF23 concentrations. However, with pathologically high FGF23 levels, Klotho acts as a molecular switch determining the type of FGF23 response.

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Role of osteokines in atherosclerosis

Liu,

Tian,

Chen

et al. 2024

Cell Biochemistry & Function

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Despite their diverse physiologies and roles, the heart, skeletal muscles, and smooth muscles all derive from a common embryonic source as bones. Moreover, bone tissue, skeletal and smooth muscles, and the heart share conserved signaling pathways. The maintenance of skeletal health is precisely regulated by osteocytes, osteoblasts, and osteoclasts through coordinated secretion of bone‐derived factors known as osteokines. Increasing evidence suggests the involvement of osteokines in regulating atherosclerotic vascular disease. Therefore, this review aims to examine the evidence for the role of osteokines in atherosclerosis development and progression comprehensively. Specifically discussed are extensively studied osteokines in atherosclerosis such as osteocalcin, osteopontin, osteoprotegerin, and fibroblast growth factor 23. Additionally, we highlighted the effects of exercise on modulating these key regulators derived from bone tissue metabolism. We believe that gaining an enhanced understanding of how osteocalcin contributes to the process of atherosclerosis will enable us to develop targeted and comprehensive therapeutic strategies against diseases associated with its progression.

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FGF23 and klotho at the intersection of kidney and cardiovascular disease

Cited by 26 publications

References 248 publications

QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

Identification of novel and distinct FGF23 signaling in a Klotho-dependent and -independent manner

Role of osteokines in atherosclerosis

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