FGF23 and klotho at the intersection of kidney and cardiovascular disease.
Journal
Nature reviews. Cardiology
ISSN: 1759-5010
Titre abrégé: Nat Rev Cardiol
Pays: England
ID NLM: 101500075
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
accepted:
13
06
2023
pubmed:
14
7
2023
medline:
14
7
2023
entrez:
14
7
2023
Statut:
ppublish
Résumé
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). As CKD progresses, CKD-specific risk factors, such as disordered mineral homeostasis, amplify traditional cardiovascular risk factors. Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis by activating complexes of FGF receptors and transmembrane klotho co-receptors. A soluble form of klotho also acts as a 'portable' FGF23 co-receptor in tissues that do not express klotho. In progressive CKD, rising circulating FGF23 levels in combination with decreasing kidney expression of klotho results in klotho-independent effects of FGF23 on the heart that promote left ventricular hypertrophy, heart failure, atrial fibrillation and death. Emerging data suggest that soluble klotho might mitigate some of these effects via several candidate mechanisms. More research is needed to investigate FGF23 excess and klotho deficiency in specific cardiovascular complications of CKD, but the pathophysiological primacy of FGF23 excess versus klotho deficiency might never be precisely resolved, given the entangled feedback loops that they share. Therefore, randomized trials should prioritize clinical practicality over scientific certainty by targeting disordered mineral homeostasis holistically in an effort to improve cardiovascular outcomes in patients with CKD.
Identifiants
pubmed: 37443358
doi: 10.1038/s41569-023-00903-0
pii: 10.1038/s41569-023-00903-0
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
11-24Informations de copyright
© 2023. Springer Nature Limited.
Références
National Institute of Diabetes and Digestive and Kidney Diseases. 2022 Annual Data Report. United States Renal Data System https://usrds-adr.niddk.nih.gov/2022 (2022).
Ortiz, A. et al. Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure. Lancet 383, 1831–1843 (2014).
pubmed: 24856028
doi: 10.1016/S0140-6736(14)60384-6
Navaneethan, S. D. et al. Prevalence, predictors, and outcomes of pulmonary hypertension in CKD. J. Am. Soc. Nephrol. 27, 877–886 (2016).
pubmed: 26386072
doi: 10.1681/ASN.2014111111
Consortium, A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat. Genet. 26, 345–348 (2000).
doi: 10.1038/81664
Shimada, T. et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc. Natl Acad. Sci. USA 98, 6500–6505 (2001).
pubmed: 11344269
pmcid: 33497
doi: 10.1073/pnas.101545198
Wolf, M. et al. Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials. J. Am. Med. Assoc. 323, 432–443 (2020).
doi: 10.1001/jama.2019.22450
Francis, F. et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat. Genet 11, 130–136 (1995).
doi: 10.1038/ng1095-130
Quarles, L. D. Endocrine functions of bone in mineral metabolism regulation. J. Clin. Invest. 118, 3820–3828 (2008).
pubmed: 19033649
pmcid: 2586800
doi: 10.1172/JCI36479
Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).
pubmed: 14966565
pmcid: 338262
doi: 10.1172/JCI200419081
Saito, H. et al. Human fibroblast growth factor-23 mutants suppress Na
pubmed: 12419819
doi: 10.1074/jbc.M207872200
Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2004).
pubmed: 15040831
doi: 10.1359/JBMR.0301264
Benet-Pages, A., Orlik, P., Strom, T. M. & Lorenz-Depiereux, B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum. Mol. Genet. 14, 385–390 (2005).
pubmed: 15590700
doi: 10.1093/hmg/ddi034
Musgrove, J. & Wolf, M. Regulation and effects of FGF23 in chronic kidney disease. Annu. Rev. Physiol. 82, 365–390 (2020).
pubmed: 31743079
doi: 10.1146/annurev-physiol-021119-034650
Ito, N. et al. Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J. Bone Miner. Metab. 25, 419–422 (2007).
pubmed: 17968495
doi: 10.1007/s00774-007-0779-3
Zhou, W. et al. Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis. J. Clin. Invest. https://doi.org/10.1172/JCI164610 (2023).
doi: 10.1172/JCI164610
pubmed: 38038129
pmcid: 10688982
Simic, P. et al. Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney. J. Clin. Invest. 130, 1513–1526 (2020).
pubmed: 32065590
pmcid: 7269595
doi: 10.1172/JCI131190
Bar, L., Stournaras, C., Lang, F. & Foller, M. Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS Lett. 593, 1879–1900 (2019).
pubmed: 31199502
doi: 10.1002/1873-3468.13494
Gattineni, J. et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am. J. Physiol. Ren. Physiol. 297, F282–F291 (2009).
doi: 10.1152/ajprenal.90742.2008
Gattineni, J., Twombley, K., Goetz, R., Mohammadi, M. & Baum, M. Regulation of serum 1,25(OH)
doi: 10.1152/ajprenal.00740.2010
Gattineni, J. et al. Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am. J. Physiol. Ren. Physiol. 306, F351–F358 (2014).
doi: 10.1152/ajprenal.00232.2013
Andrukhova, O. et al. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway. Bone 51, 621–628 (2012).
pubmed: 22647968
pmcid: 3419258
doi: 10.1016/j.bone.2012.05.015
Edmonston, D. & Wolf, M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat. Rev. Nephrol. 16, 7–19 (2020).
pubmed: 31519999
doi: 10.1038/s41581-019-0189-5
Goetz, R. et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-klotho complex formation. Proc. Natl Acad. Sci. USA 107, 407–412 (2010).
pubmed: 19966287
doi: 10.1073/pnas.0902006107
Wolf, M., Koch, T. A. & Bregman, D. B. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J. Bone Miner. Res. 28, 1793–1803 (2013).
pubmed: 23505057
doi: 10.1002/jbmr.1923
Goetz, R. & Mohammadi, M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat. Rev. Mol. Cell Biol. 14, 166–180 (2013).
pubmed: 23403721
pmcid: 3695728
doi: 10.1038/nrm3528
Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).
pubmed: 9363890
doi: 10.1038/36285
Nakatani, T. et al. In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis. FASEB J. 23, 433–441 (2009).
pubmed: 18835926
pmcid: 2630784
doi: 10.1096/fj.08-114397
Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).
pubmed: 17086194
doi: 10.1038/nature05315
Bai, X., Dinghong, Q., Miao, D., Goltzman, D. & Karaplis, A. C. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a klotho-deficient phenotype. Am. J. Physiol. Endocrinol. Metab. 296, E79–E88 (2009).
pubmed: 18984852
doi: 10.1152/ajpendo.90539.2008
Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).
pubmed: 16436388
doi: 10.1074/jbc.C500457200
Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).
pubmed: 17992255
pmcid: 2066196
Lim, K. et al. α-Klotho expression in human tissues. J. Clin. Endocrinol. Metab. 100, E1308–E1318 (2015).
pubmed: 26280509
pmcid: 4596032
doi: 10.1210/jc.2015-1800
Hu, M. C. et al. Renal production, uptake, and handling of circulating αKlotho. J. Am. Soc. Nephrol. 27, 79–90 (2016).
pubmed: 25977312
doi: 10.1681/ASN.2014101030
Lindberg, K. et al. The kidney is the principal organ mediating klotho effects. J. Am. Soc. Nephrol. 25, 2169–2175 (2014).
pubmed: 24854271
pmcid: 4178446
doi: 10.1681/ASN.2013111209
Chen, C. D., Podvin, S., Gillespie, E., Leeman, S. E. & Abraham, C. R. Insulin stimulates the cleavage and release of the extracellular domain of klotho by ADAM10 and ADAM17. Proc. Natl Acad. Sci. USA 104, 19796–19801 (2007).
doi: 10.1073/pnas.0709805104
Bloch, L. et al. Klotho is a substrate for α-, β- and γ-secretase. FEBS Lett. 583, 3221–3224 (2009).
pubmed: 19737556
pmcid: 2757472
doi: 10.1016/j.febslet.2009.09.009
van Loon, E. P. et al. Shedding of klotho by ADAMs in the kidney. Am. J. Physiol. Ren. Physiol. 309, F359–F368 (2015).
doi: 10.1152/ajprenal.00240.2014
Chen, C. D. et al. Identification of the cleavage sites leading to the shed forms of human and mouse anti-aging and cognition-enhancing protein klotho. PLoS ONE 15, e0226382 (2020).
pubmed: 31929539
pmcid: 6957300
doi: 10.1371/journal.pone.0226382
Neyra, J. A. et al. Performance of soluble klotho assays in clinical samples of kidney disease. Clin. Kidney J. 13, 235–244 (2020).
pubmed: 32297879
doi: 10.1093/ckj/sfz085
Mencke, R. et al. Human alternative klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI Insight 2, e94375 (2017).
pubmed: 29046474
pmcid: 5846909
doi: 10.1172/jci.insight.94375
Roig-Soriano, J. et al. Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure. Sci. Rep. 13, 4211 (2023).
pubmed: 36918615
pmcid: 10014869
doi: 10.1038/s41598-023-31117-6
Richter, B. & Faul, C. FGF23 actions on target tissues – with and without klotho. Front. Endocrinol. 9, 189 (2018).
doi: 10.3389/fendo.2018.00189
Dalton, G. et al. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc. Natl Acad. Sci. USA 114, 752–757 (2017).
pubmed: 28069944
pmcid: 5278494
doi: 10.1073/pnas.1620301114
Wright, J. D., An, S. W., Xie, J., Lim, C. & Huang, C. L. Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway. FASEB J. 33, 9182–9193 (2019).
pubmed: 31063704
pmcid: 6662984
doi: 10.1096/fj.201900321R
Juppner, H. & Wolf, M. αKlotho: FGF23 coreceptor and FGF23-regulating hormone. J. Clin. Invest. 122, 4336–4339 (2012).
pubmed: 23187136
pmcid: 3533569
doi: 10.1172/JCI67055
Smith, R. C. et al. Circulating αKlotho influences phosphate handling by controlling FGF23 production. J. Clin. Invest. 122, 4710–4715 (2012).
pubmed: 23187128
pmcid: 3533557
doi: 10.1172/JCI64986
Chen, G. et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553, 461–466 (2018).
pubmed: 29342138
pmcid: 6007875
doi: 10.1038/nature25451
Grabner, A. et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 22, 1020–1032 (2015).
pubmed: 26437603
pmcid: 4670583
doi: 10.1016/j.cmet.2015.09.002
Smith, E. R., Holt, S. G. & Hewitson, T. D. FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction. Int. J. Biochem. Cell Biol. 92, 63–78 (2017).
pubmed: 28919046
doi: 10.1016/j.biocel.2017.09.009
Yanucil, C. et al. Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease. Kidney Int. 102, 261–279 (2022).
pubmed: 35513125
pmcid: 9329240
doi: 10.1016/j.kint.2022.03.028
Grabner, A. & Faul, C. The role of fibroblast growth factor 23 and klotho in uremic cardiomyopathy. Curr. Opin. Nephrol. Hypertens. 25, 314–324 (2016).
pubmed: 27219043
pmcid: 4891254
doi: 10.1097/MNH.0000000000000231
Courbon, G. et al. Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease. Bone Res. 9, 35 (2021).
pubmed: 34334787
pmcid: 8326281
doi: 10.1038/s41413-021-00154-0
David, V. et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 89, 135–146 (2016).
pubmed: 26535997
pmcid: 4854810
doi: 10.1038/ki.2015.290
Perwad, F. et al. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146, 5358–5364 (2005).
pubmed: 16123154
doi: 10.1210/en.2005-0777
Hu, M. C. et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 22, 124–136 (2011).
pubmed: 21115613
pmcid: 3014041
doi: 10.1681/ASN.2009121311
Thompson, S. et al. Cause of death in patients with reduced kidney function. J. Am. Soc. Nephrol. 26, 2504–2511 (2015).
pubmed: 25733525
pmcid: 4587695
doi: 10.1681/ASN.2014070714
Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008).
pubmed: 18687639
pmcid: 2890264
doi: 10.1056/NEJMoa0706130
Isakova, T. et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. J. Am. Med. Assoc. 305, 2432–2439 (2011).
doi: 10.1001/jama.2011.826
Komaba, H. et al. Fibroblast growth factor 23 and mortality among prevalent hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns study. Kidney Int. Rep. 5, 1956–1964 (2020).
pubmed: 33163716
pmcid: 7609896
doi: 10.1016/j.ekir.2020.08.013
Sharma, S. et al. FGF23 and cause-specific mortality in community-living individuals – the Health, Aging, and Body Composition study. J. Am. Geriatr. Soc. 69, 711–717 (2021).
pubmed: 33170519
doi: 10.1111/jgs.16910
Souma, N. et al. Fibroblast growth factor 23 and cause-specific mortality in the general population: the Northern Manhattan study. J. Clin. Endocrinol. Metab. 101, 3779–3786 (2016).
pubmed: 27501282
pmcid: 5052338
doi: 10.1210/jc.2016-2215
Liu, M. et al. Fibroblast growth factor-23 and the risk of cardiovascular diseases and mortality in the general population: a systematic review and dose-response meta-analysis. Front. Cardiovasc. Med. 9, 989574 (2022).
pubmed: 36407457
pmcid: 9669381
doi: 10.3389/fcvm.2022.989574
Isakova, T. et al. Longitudinal FGF23 trajectories and mortality in patients with CKD. J. Am. Soc. Nephrol. 29, 579–590 (2018).
pubmed: 29167351
doi: 10.1681/ASN.2017070772
Kang, M. et al. In-center nocturnal hemodialysis reduced the circulating FGF23, left ventricular hypertrophy, and all-cause mortality: a retrospective cohort study. Front. Med. 9, 912764 (2022).
doi: 10.3389/fmed.2022.912764
Moe, S. M. et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. Circulation 132, 27–39 (2015).
pubmed: 26059012
doi: 10.1161/CIRCULATIONAHA.114.013876
Macdougall, I. C. et al. Intravenous iron in patients undergoing maintenance hemodialysis. N. Engl. J. Med. 380, 447–458 (2019).
pubmed: 30365356
doi: 10.1056/NEJMoa1810742
Vergaro, G. et al. Discharge FGF23 level predicts one year outcome in patients admitted with acute heart failure. Int. J. Cardiol. 336, 98–104 (2021).
pubmed: 34019969
doi: 10.1016/j.ijcard.2021.05.028
Poelzl, G. et al. FGF23 is associated with disease severity and prognosis in chronic heart failure. Eur. J. Clin. Invest. 44, 1150–1158 (2014).
pubmed: 25294008
doi: 10.1111/eci.12349
Gruson, D. et al. C-terminal FGF23 is a strong predictor of survival in systolic heart failure. Peptides 37, 258–262 (2012).
pubmed: 22902597
doi: 10.1016/j.peptides.2012.08.003
von Jeinsen, B. et al. Bone marrow and plasma FGF-23 in heart failure patients: novel insights into the heart–bone axis. ESC Heart Fail. 6, 536–544 (2019).
doi: 10.1002/ehf2.12416
Plischke, M. et al. Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure. Eur. J. Clin. Invest. 42, 649–656 (2012).
pubmed: 22150123
doi: 10.1111/j.1365-2362.2011.02631.x
Kanagala, P. et al. Fibroblast-growth-factor-23 in heart failure with preserved ejection fraction: relation to exercise capacity and outcomes. ESC Heart Fail. 7, 4089–4099 (2020).
pubmed: 32935918
pmcid: 7755022
doi: 10.1002/ehf2.13020
Roy, C. et al. Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction. ESC Heart Fail. 7, 2494–2507 (2020).
pubmed: 32578967
pmcid: 7524237
doi: 10.1002/ehf2.12816
Wohlfahrt, P. et al. Association of fibroblast growth factor-23 levels and angiotensin-converting enzyme inhibition in chronic systolic heart failure. JACC Heart Fail. 3, 829–839 (2015).
pubmed: 26450001
doi: 10.1016/j.jchf.2015.05.012
Yan, Y. & Chen, J. Association between serum klotho concentration and all-cause and cardiovascular mortality among American individuals with hypertension. Front. Cardiovasc. Med. 9, 1013747 (2022).
pubmed: 36457804
pmcid: 9705974
doi: 10.3389/fcvm.2022.1013747
Kresovich, J. K. & Bulka, C. M. Low serum klotho associated with all-cause mortality among a nationally representative sample of American adults. J. Gerontol. A Biol. Sci. Med. Sci. 77, 452–456 (2022).
pubmed: 34628493
doi: 10.1093/gerona/glab308
Seiler, S. et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin. J. Am. Soc. Nephrol. 9, 1049–1058 (2014).
pubmed: 24677555
pmcid: 4046724
doi: 10.2215/CJN.07870713
Brandenburg, V. M. et al. Soluble klotho and mortality: the Ludwigshafen Risk and Cardiovascular Health study. Atherosclerosis 242, 483–489 (2015).
pubmed: 26298739
doi: 10.1016/j.atherosclerosis.2015.08.017
Memmos, E. et al. Soluble klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol. 20, 217 (2019).
pubmed: 31185930
pmcid: 6560885
doi: 10.1186/s12882-019-1391-1
Ko, G. J. et al. The association of klotho gene polymorphism with the mortality of patients on maintenance dialysis. Clin. Nephrol. 80, 263–269 (2013).
pubmed: 23993164
doi: 10.5414/CN107800
Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393–4408 (2011).
pubmed: 21985788
pmcid: 3204831
doi: 10.1172/JCI46122
Unger, E. D. et al. Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction. Eur. J. Heart Fail. 18, 103–112 (2016).
pubmed: 26635076
doi: 10.1002/ejhf.445
Di Marco, G. S. et al. Cardioprotective effect of calcineurin inhibition in an animal model of renal disease. Eur. Heart J. 32, 1935–1945 (2011).
pubmed: 21138940
doi: 10.1093/eurheartj/ehq436
Hu, M. C. et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J. Am. Soc. Nephrol. 26, 1290–1302 (2015).
pubmed: 25326585
doi: 10.1681/ASN.2014050465
Kieswich, J. E. et al. A novel model of reno-cardiac syndrome in the C57BL/6 mouse strain. BMC Nephrol. 19, 346 (2018).
pubmed: 30509210
pmcid: 6278034
doi: 10.1186/s12882-018-1155-3
Olauson, H., Mencke, R., Hillebrands, J. L. & Larsson, T. E. Tissue expression and source of circulating αKlotho. Bone 100, 19–35 (2017).
pubmed: 28323144
doi: 10.1016/j.bone.2017.03.043
Wilkins, B. J. et al. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ. Res. 94, 110–118 (2004).
pubmed: 14656927
doi: 10.1161/01.RES.0000109415.17511.18
Leifheit-Nestler, M. et al. Fibroblast growth factor 23 is induced by an activated renin–angiotensin–aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts. Nephrol. Dial. Transpl. 33, 1722–1734 (2018).
doi: 10.1093/ndt/gfy006
Lee, T. W. et al. Fibroblast growth factor 23 stimulates cardiac fibroblast activity through phospholipase C-mediated calcium signaling. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23010166 (2021).
doi: 10.3390/ijms23010166
pubmed: 35008852
pmcid: 8745242
Kuga, K. et al. Fibrosis growth factor 23 is a promoting factor for cardiac fibrosis in the presence of transforming growth factor-β1. PLoS ONE 15, e0231905 (2020).
pubmed: 32315372
pmcid: 7173860
doi: 10.1371/journal.pone.0231905
Touchberry, C. D. et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am. J. Physiol. Endocrinol. Metab. 304, E863–E873 (2013).
pubmed: 23443925
pmcid: 3625783
doi: 10.1152/ajpendo.00596.2012
Grabner, A. et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci. Rep. 7, 1993 (2017).
pubmed: 28512310
pmcid: 5434018
doi: 10.1038/s41598-017-02068-6
Navarro-Garcia, J. A. et al. Fibroblast growth factor-23 promotes rhythm alterations and contractile dysfunction in adult ventricular cardiomyocytes. Nephrol. Dial. Transpl. 34, 1864–1875 (2019).
doi: 10.1093/ndt/gfy392
Verkaik, M. et al. High fibroblast growth factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes. Physiol. Rep. 6, e13591 (2018).
pubmed: 29611320
pmcid: 5880876
doi: 10.14814/phy2.13591
Andrukhova, O. et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol. Med. 6, 744–759 (2014).
pubmed: 24797667
pmcid: 4203353
doi: 10.1002/emmm.201303716
Dai, B. et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS ONE 7, e44161 (2012).
pubmed: 22970174
pmcid: 3435395
doi: 10.1371/journal.pone.0044161
Han, X. et al. Cardiovascular effects of renal distal tubule deletion of the FGF receptor 1 gene. J. Am. Soc. Nephrol. 29, 69–80 (2018).
pubmed: 28993502
doi: 10.1681/ASN.2017040412
Bockmann, I. et al. FGF23-mediated activation of local RAAS promotes cardiac hypertrophy and fibrosis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20184634 (2019).
doi: 10.3390/ijms20184634
pubmed: 31540546
pmcid: 6770314
Mhatre, K. N. et al. Crosstalk between FGF23- and angiotensin II-mediated Ca
pubmed: 30062428
doi: 10.1007/s00018-018-2885-x
Singh, S. et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 90, 985–996 (2016).
pubmed: 27457912
pmcid: 5065745
doi: 10.1016/j.kint.2016.05.019
Coe, L. M. et al. FGF-23 is a negative regulator of prenatal and postnatal erythropoiesis. J. Biol. Chem. 289, 9795–9810 (2014).
pubmed: 24509850
pmcid: 3975025
doi: 10.1074/jbc.M113.527150
Agoro, R. et al. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. FASEB J. 32, 3752–3764 (2018).
pubmed: 29481308
pmcid: 5998980
doi: 10.1096/fj.201700667R
Han, X., Cai, C., Xiao, Z. & Quarles, L. D. FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble klotho in mice. J. Mol. Cell Cardiol. 138, 66–74 (2020).
pubmed: 31758962
doi: 10.1016/j.yjmcc.2019.11.149
Francis, C. et al. Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease. Kidney Int. 96, 1346–1358 (2019).
pubmed: 31668632
pmcid: 6875640
doi: 10.1016/j.kint.2019.07.026
Falkner, B., Keith, S. W., Gidding, S. S. & Langman, C. B. Fibroblast growth factor-23 is independently associated with cardiac mass in African-American adolescent males. J. Am. Soc. Hypertens. 11, 480–487 (2017).
pubmed: 28456498
pmcid: 5550349
doi: 10.1016/j.jash.2017.04.001
Agarwal, I. et al. Fibroblast growth factor-23 and cardiac structure and function. J. Am. Heart Assoc. 3, e000584 (2014).
pubmed: 24525546
pmcid: 3959672
doi: 10.1161/JAHA.113.000584
Akhabue, E. et al. Fibroblast growth factor-23 and subclinical markers of cardiac dysfunction: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Am. Heart J. 245, 10–18 (2022).
pubmed: 34861237
doi: 10.1016/j.ahj.2021.11.009
Patel, R. B. et al. Fibroblast growth factor 23 and long-term cardiac function: the multi-ethnic study of atherosclerosis. Circ. Cardiovasc. Imaging 13, e011925 (2020).
pubmed: 33161733
pmcid: 7665116
doi: 10.1161/CIRCIMAGING.120.011925
Mirza, M. A., Larsson, A., Melhus, H., Lind, L. & Larsson, T. E. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207, 546–551 (2009).
pubmed: 19524924
doi: 10.1016/j.atherosclerosis.2009.05.013
Jovanovich, A. et al. Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. Atherosclerosis 231, 114–119 (2013).
pubmed: 24125420
doi: 10.1016/j.atherosclerosis.2013.09.002
Gutierrez, O. M. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119, 2545–2552 (2009).
pubmed: 19414634
pmcid: 2740903
doi: 10.1161/CIRCULATIONAHA.108.844506
Mitsnefes, M. M. et al. FGF23 and left ventricular hypertrophy in children with CKD. Clin. J. Am. Soc. Nephrol. 13, 45–52 (2018).
pubmed: 29025789
doi: 10.2215/CJN.02110217
Negishi, K. et al. Association between fibroblast growth factor 23 and left ventricular hypertrophy in maintenance hemodialysis patients. Comparison with B-type natriuretic peptide and cardiac troponin T. Circ. J. 74, 2734–2740 (2010).
pubmed: 21041973
doi: 10.1253/circj.CJ-10-0355
Leifheit-Nestler, M. et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol. Dial. Transpl. 31, 1088–1099 (2016).
doi: 10.1093/ndt/gfv421
Henry, A. et al. Therapeutic targets for heart failure identified using proteomics and Mendelian randomization. Circulation 145, 1205–1217 (2022).
pubmed: 35300523
pmcid: 9010023
doi: 10.1161/CIRCULATIONAHA.121.056663
Ix, J. H. et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J. Am. Coll. Cardiol. 60, 200–207 (2012).
pubmed: 22703926
pmcid: 3396791
doi: 10.1016/j.jacc.2012.03.040
Kestenbaum, B. et al. Fibroblast growth factor-23 and cardiovascular disease in the general population: the multi-ethnic study of atherosclerosis. Circ. Heart Fail. 7, 409–417 (2014).
pubmed: 24668259
pmcid: 4031265
doi: 10.1161/CIRCHEARTFAILURE.113.000952
Lutsey, P. L. et al. Fibroblast growth factor-23 and incident coronary heart disease, heart failure, and cardiovascular mortality: the atherosclerosis risk in communities study. J. Am. Heart Assoc. 3, e000936 (2014).
pubmed: 24922628
pmcid: 4309096
doi: 10.1161/JAHA.114.000936
Scialla, J. J. et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J. Am. Soc. Nephrol. 25, 349–360 (2014).
pubmed: 24158986
doi: 10.1681/ASN.2013050465
Binnenmars, S. H. et al. Fibroblast growth factor 23 and risk of new onset heart failure with preserved or reduced ejection fraction: the PREVEND study. J. Am. Heart Assoc. 11, e024952 (2022).
pubmed: 35876420
pmcid: 9375507
doi: 10.1161/JAHA.121.024952
Paul, S. et al. Fibroblast growth factor 23 and incident cardiovascular disease and mortality in middle-aged adults. J. Am. Heart Assoc. 10, e020196 (2021).
pubmed: 34387090
pmcid: 8475041
doi: 10.1161/JAHA.120.020196
Janus, S. E. et al. Multi-variable biomarker approach in identifying incident heart failure in chronic kidney disease: results from the Chronic Renal Insufficiency Cohort study. Eur. J. Heart Fail. 24, 988–995 (2022).
pubmed: 35587997
doi: 10.1002/ejhf.2543
Ghuman, J. et al. Fibroblast growth factor 23 and exercise capacity in heart failure with preserved ejection fraction. J. Card. Fail. 27, 309–317 (2021).
pubmed: 33035687
doi: 10.1016/j.cardfail.2020.09.477
Cornelissen, A. et al. Intact fibroblast growth factor 23 levels and outcome prediction in patients with acute heart failure. Sci. Rep. 11, 15507 (2021).
pubmed: 34330955
pmcid: 8324826
doi: 10.1038/s41598-021-94780-7
Koller, L. et al. Fibroblast growth factor 23 is an independent and specific predictor of mortality in patients with heart failure and reduced ejection fraction. Circ. Heart Fail. 8, 1059–1067 (2015).
pubmed: 26273098
doi: 10.1161/CIRCHEARTFAILURE.115.002341
Dorr, K. et al. Randomized trial of etelcalcetide for cardiac hypertrophy in hemodialysis. Circ. Res. 128, 1616–1625 (2021).
pubmed: 33825489
doi: 10.1161/CIRCRESAHA.120.318556
Marthi, A. et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J. Am. Soc. Nephrol. 29, 2015–2027 (2018).
pubmed: 29764921
pmcid: 6050929
doi: 10.1681/ASN.2017121334
Carpenter, T. O. et al. Burosumab therapy in children with X-linked hypophosphatemia. N. Engl. J. Med. 378, 1987–1998 (2018).
pubmed: 29791829
doi: 10.1056/NEJMoa1714641
Takashi, Y. et al. Patients with FGF23-related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy. Endocr. Res. 42, 132–137 (2017).
pubmed: 27754732
doi: 10.1080/07435800.2016.1242604
Hernandez-Frias, O. et al. Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia. Pediatr. Nephrol. 34, 1077–1086 (2019).
pubmed: 30607568
doi: 10.1007/s00467-018-4180-3
Nehgme, R., Fahey, J. T., Smith, C. & Carpenter, T. O. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J. Clin. Endocrinol. Metab. 82, 2450–2454 (1997).
pubmed: 9253316
doi: 10.1210/jcem.82.8.4181
Carpenter, T. O. et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J. Clin. Endocrinol. Metab. 95, E352–E357 (2010).
pubmed: 20685863
pmcid: 2968736
doi: 10.1210/jc.2010-0589
Liang, Y., Luo, S., Schooling, C. M. & Au Yeung, S. L. Genetically predicted fibroblast growth factor 23 and major cardiovascular diseases, their risk factors, kidney function, and longevity: a two-sample Mendelian randomization study. Front. Genet. 12, 699455 (2021).
pubmed: 34367258
pmcid: 8343174
doi: 10.3389/fgene.2021.699455
Akwo, E. et al. Association of genetically predicted fibroblast growth factor-23 with heart failure: a Mendelian randomization study. Clin. J. Am. Soc. Nephrol. 17, 1183–1193 (2022).
pubmed: 35902130
pmcid: 9435988
doi: 10.2215/CJN.00960122
Xie, J., Yoon, J., An, S. W., Kuro-o, M. & Huang, C. L. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. J. Am. Soc. Nephrol. 26, 1150–1160 (2015).
pubmed: 25475745
doi: 10.1681/ASN.2014040325
Yang, K. et al. Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J. Am. Soc. Nephrol. 26, 2434–2446 (2015).
pubmed: 25804281
pmcid: 4587686
doi: 10.1681/ASN.2014060543
Hu, M. C. et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 91, 1104–1114 (2017).
pubmed: 28131398
pmcid: 5592833
doi: 10.1016/j.kint.2016.10.034
Navarro-Garcia, J. A. et al. Enhanced klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca
pubmed: 32830863
pmcid: 7520447
doi: 10.1111/bph.15235
Zhu, H., Gao, Y., Zhu, S., Cui, Q. & Du, J. Klotho improves cardiac function by suppressing reactive oxygen species (ROS) mediated apoptosis by modulating Mapks/Nrf2 signaling in doxorubicin-induced cardiotoxicity. Med. Sci. Monit. 23, 5283–5293 (2017).
pubmed: 29107939
pmcid: 5687120
doi: 10.12659/MSM.907449
Xiao, Z. et al. FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model. JCI Insight 4, e132820 (2019).
pubmed: 31801907
pmcid: 6962016
doi: 10.1172/jci.insight.132820
Guo, Y. et al. Klotho protects the heart from hyperglycemia-induced injury by inactivating ROS and NF-κB-mediated inflammation both in vitro and in vivo. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 238–251 (2018).
pubmed: 28982613
doi: 10.1016/j.bbadis.2017.09.029
Liu, Q. et al. The axis of local cardiac endogenous klotho-TGF-β1-Wnt signaling mediates cardiac fibrosis in human. J. Mol. Cell Cardiol. 136, 113–124 (2019).
pubmed: 31520610
doi: 10.1016/j.yjmcc.2019.09.004
Xie, J. et al. Cardioprotection by klotho through downregulation of TRPC6 channels in the mouse heart. Nat. Commun. 3, 1238 (2012).
pubmed: 23212367
doi: 10.1038/ncomms2240
Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).
pubmed: 17099778
pmcid: 1635163
doi: 10.1172/JCI27702
Lorenz, K., Schmitt, J. P., Schmitteckert, E. M. & Lohse, M. J. A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nat. Med. 15, 75–83 (2009).
pubmed: 19060905
doi: 10.1038/nm.1893
Bueno, O. F. et al. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341–6350 (2000).
pubmed: 11101507
pmcid: 305855
doi: 10.1093/emboj/19.23.6341
Purcell, N. H. et al. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc. Natl Acad. Sci. USA 104, 14074–14079 (2007).
pubmed: 17709754
pmcid: 1955824
doi: 10.1073/pnas.0610906104
Harris, I. S. et al. Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation 110, 718–723 (2004).
pubmed: 15289381
doi: 10.1161/01.CIR.0000138190.50127.6A
Sun, Y. et al. Beclin-1-dependent autophagy protects the heart during sepsis. Circulation 138, 2247–2262 (2018).
pubmed: 29853517
pmcid: 6274625
doi: 10.1161/CIRCULATIONAHA.117.032821
Kim, H. R. et al. Circulating α-klotho levels in CKD and relationship to progression. Am. J. Kidney Dis. 61, 899–909 (2013).
pubmed: 23540260
doi: 10.1053/j.ajkd.2013.01.024
Tanaka, S., Fujita, S., Kizawa, S., Morita, H. & Ishizaka, N. Association between FGF23, α-Klotho, and cardiac abnormalities among patients with various chronic kidney disease stages. PLoS ONE 11, e0156860 (2016).
pubmed: 27400031
pmcid: 4939955
doi: 10.1371/journal.pone.0156860
Taneike, M. et al. Alpha-Klotho is a novel predictor of treatment responsiveness in patients with heart failure. Sci. Rep. 11, 2058 (2021).
pubmed: 33479413
pmcid: 7820312
doi: 10.1038/s41598-021-81517-9
Bergmark, B. A. et al. Klotho, fibroblast growth factor-23, and the renin-angiotensin system – an analysis from the PEACE trial. Eur. J. Heart Fail. 21, 462–470 (2019).
pubmed: 30773798
doi: 10.1002/ejhf.1424
Shibata, K. et al. Association between circulating fibroblast growth factor 23, α-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS ONE 8, e73184 (2013).
pubmed: 24039882
pmcid: 3767778
doi: 10.1371/journal.pone.0073184
Buiten, M. S. et al. Soluble klotho is not independently associated with cardiovascular disease in a population of dialysis patients. BMC Nephrol. 15, 197 (2014).
pubmed: 25495997
pmcid: 4293085
doi: 10.1186/1471-2369-15-197
Sellier, A. B. et al. FGFR4 and klotho polymorphisms are not associated with cardiovascular outcomes in chronic kidney disease. Am. J. Nephrol. 52, 808–816 (2021).
pubmed: 34673637
doi: 10.1159/000519274
Sun, X., Chen, L., He, Y. & Zheng, L. Circulating α-Klotho levels in relation to cardiovascular diseases: a Mendelian randomization study. Front. Endocrinol. 13, 842846 (2022).
doi: 10.3389/fendo.2022.842846
Zhu, X. et al. Renal function mediates the association between klotho and congestive heart failure among middle-aged and older individuals. Front. Cardiovasc. Med. 9, 802287 (2022).
pubmed: 35509269
pmcid: 9058082
doi: 10.3389/fcvm.2022.802287
London, G. M. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol. Dial. Transpl. 18, 1731–1740 (2003).
doi: 10.1093/ndt/gfg414
Jono, S. et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ. Res. 87, E10–E17 (2000).
pubmed: 11009570
doi: 10.1161/01.RES.87.7.e10
Silswal, N. et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am. J. Physiol. Endocrinol. Metab. 307, E426–E436 (2014).
pubmed: 25053401
pmcid: 4154070
doi: 10.1152/ajpendo.00264.2014
Richter, B., Haller, J., Haffner, D. & Leifheit-Nestler, M. Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflug. Arch. 468, 1621–1635 (2016).
doi: 10.1007/s00424-016-1858-x
Chung, C. P. et al. α-Klotho expression determines nitric oxide synthesis in response to FGF-23 in human aortic endothelial cells. PLoS ONE 12, e0176817 (2017).
pubmed: 28463984
pmcid: 5413063
doi: 10.1371/journal.pone.0176817
Verkaik, M. et al. FGF23 impairs peripheral microvascular function in renal failure. Am. J. Physiol. Heart Circ. Physiol. 315, H1414–H1424 (2018).
pubmed: 30028196
doi: 10.1152/ajpheart.00272.2018
Six, I. et al. Direct, acute effects of klotho and FGF23 on vascular smooth muscle and endothelium. PLoS ONE 9, e93423 (2014).
pubmed: 24695641
pmcid: 3973676
doi: 10.1371/journal.pone.0093423
Lindberg, K. et al. Arterial klotho expression and FGF23 effects on vascular calcification and function. PLoS ONE 8, e60658 (2013).
pubmed: 23577141
pmcid: 3618102
doi: 10.1371/journal.pone.0060658
Shalhoub, V. et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J. Clin. Invest. 122, 2543–2553 (2012).
pubmed: 22728934
pmcid: 3386816
doi: 10.1172/JCI61405
Sarmento-Dias, M. et al. Fibroblast growth factor 23 is associated with left ventricular hypertrophy, not with uremic vasculopathy in peritoneal dialysis patients. Clin. Nephrol. 85, 135–141 (2016).
pubmed: 26833300
doi: 10.5414/CN108716
Panwar, B. et al. Association of fibroblast growth factor 23 with risk of incident coronary heart disease in community-living adults. JAMA Cardiol. 3, 318–325 (2018).
pubmed: 29516098
pmcid: 5875372
doi: 10.1001/jamacardio.2018.0139
Yokomoto-Umakoshi, M. et al. Investigating the causal effect of fibroblast growth factor 23 on osteoporosis and cardiometabolic disorders: a Mendelian randomization study. Bone 143, 115777 (2021).
pubmed: 33253933
doi: 10.1016/j.bone.2020.115777
Hum, J. M. et al. Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho. J. Am. Soc. Nephrol. 28, 1162–1174 (2017).
pubmed: 27837149
doi: 10.1681/ASN.2015111266
Ohnishi, M., Nakatani, T., Lanske, B. & Razzaque, M. S. Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1α-hydroxylase. Kidney Int. 75, 1166–1172 (2009).
pubmed: 19225558
pmcid: 3143194
doi: 10.1038/ki.2009.24
Cheng, L., Zhang, L., Yang, J. & Hao, L. Activation of peroxisome proliferator-activated receptor γ inhibits vascular calcification by upregulating klotho. Exp. Ther. Med. 13, 467–474 (2017).
pubmed: 28352317
doi: 10.3892/etm.2016.3996
Chang, J. R. et al. Intermedin
pubmed: 26880455
doi: 10.1016/j.kint.2015.12.029
Zhao, Y. et al. Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via klotho upregulation. Kidney Int. 88, 711–721 (2015).
pubmed: 26061549
doi: 10.1038/ki.2015.160
Lau, W. L. et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 82, 1261–1270 (2012).
pubmed: 22932118
pmcid: 3511664
doi: 10.1038/ki.2012.322
Nagai, R. et al. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol. Life Sci. 57, 738–746 (2000).
pubmed: 10892340
doi: 10.1007/s000180050038
Maltese, G. et al. The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells. J. Cell Mol. Med. 21, 621–627 (2017).
pubmed: 27696667
doi: 10.1111/jcmm.12996
Kusaba, T. et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca
pubmed: 20966350
pmcid: 2984167
doi: 10.1073/pnas.1008544107
Kawarazaki, W. et al. Salt causes aging-associated hypertension via vascular Wnt5a under klotho deficiency. J. Clin. Invest. 130, 4152–4166 (2020).
pubmed: 32597829
pmcid: 7410076
Cui, W., Leng, B., Liu, W. & Wang, G. Suppression of apoptosis in human umbilical vein endothelial cells (HUVECs) by klotho protein is associated with reduced endoplasmic reticulum oxidative stress and activation of the PI3K/AKT pathway. Med. Sci. Monit. 24, 8489–8499 (2018).
pubmed: 30471224
pmcid: 6270887
doi: 10.12659/MSM.911202
Ikushima, M. et al. Anti-apoptotic and anti-senescence effects of klotho on vascular endothelial cells. Biochem. Biophys. Res. Commun. 339, 827–832 (2006).
pubmed: 16325773
doi: 10.1016/j.bbrc.2005.11.094
Yang, K. et al. Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. Blood 129, 2667–2679 (2017).
pubmed: 28264799
doi: 10.1182/blood-2016-10-744060
Mencke, R. et al. Membrane-bound klotho is not expressed endogenously in healthy or uraemic human vascular tissue. Cardiovasc. Res. 108, 220–231 (2015).
pubmed: 26116633
doi: 10.1093/cvr/cvv187
Savvoulidis, P. et al. Calcification of coronary arteries and aortic valve and circulating a-klotho levels in patients with chronic kidney disease. J. Thorac. Dis. 12, 431–437 (2020).
pubmed: 32274109
pmcid: 7139066
doi: 10.21037/jtd.2020.01.49
Liu, Q., Yu, L., Yin, X., Ye, J. & Li, S. Correlation between soluble klotho and vascular calcification in chronic kidney disease: a meta-analysis and systematic review. Front. Physiol. 12, 711904 (2021).
pubmed: 34483963
pmcid: 8414804
doi: 10.3389/fphys.2021.711904
Solache-Berrocal, G. et al. CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events. Nephrol. Dial. Transpl. 36, 2076–2083 (2021).
doi: 10.1093/ndt/gfaa240
Valdivielso, J. M. et al. Association of the rs495392 klotho polymorphism with atheromatosis progression in patients with chronic kidney disease. Nephrol. Dial. Transpl. 34, 2079–2088 (2019).
doi: 10.1093/ndt/gfy207
Lee, J. et al. Association between serum klotho levels and cardiovascular disease risk factors in older adults. BMC Cardiovasc. Disord. 22, 442 (2022).
pubmed: 36221064
pmcid: 9552482
doi: 10.1186/s12872-022-02885-2
Alonso, A. et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 123, 2946–2953 (2011).
pubmed: 21646496
pmcid: 3139978
doi: 10.1161/CIRCULATIONAHA.111.020982
Wizemann, V. et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 77, 1098–1106 (2010).
pubmed: 20054291
doi: 10.1038/ki.2009.477
Mehta, R. et al. Association of fibroblast growth factor 23 with atrial fibrillation in chronic kidney disease, from the chronic renal insufficiency cohort study. JAMA Cardiol. 1, 548–556 (2016).
pubmed: 27434583
pmcid: 4992989
doi: 10.1001/jamacardio.2016.1445
Chua, W. et al. 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. PLoS Med. 18, e1003405 (2021).
pubmed: 33534825
pmcid: 7857735
doi: 10.1371/journal.pmed.1003405
Mathew, J. S. et al. Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Circulation 130, 298–307 (2014).
pubmed: 24920722
pmcid: 4108550
doi: 10.1161/CIRCULATIONAHA.113.005499
Chua, W. et al. Data-driven discovery and validation of circulating blood-based biomarkers associated with prevalent atrial fibrillation. Eur. Heart J. 40, 1268–1276 (2019).
pubmed: 30615112
pmcid: 6475521
doi: 10.1093/eurheartj/ehy815
Tan, Z. et al. Relationship between serum growth differentiation factor 15, fibroblast growth factor-23 and risk of atrial fibrillation: a systematic review and meta-analysis. Front. Cardiovasc. Med. 9, 899667 (2022).
pubmed: 35990956
pmcid: 9386045
doi: 10.3389/fcvm.2022.899667
Huang, S. Y. et al. Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes. Oncotarget 7, 69231–69242 (2016).
pubmed: 27713141
pmcid: 5342473
doi: 10.18632/oncotarget.12470
Kao, Y. H. et al. FGF-23 dysregulates calcium homeostasis and electrophysiological properties in HL-1 atrial cells. Eur. J. Clin. Invest. 44, 795–801 (2014).
pubmed: 24942561
doi: 10.1111/eci.12296
Lu, Y. Y. et al. Fibroblast growth factor 1 reduces pulmonary vein and atrium arrhythmogenesis via modification of oxidative stress and sodium/calcium homeostasis. Front. Cardiovasc. Med. 8, 813589 (2021).
pubmed: 35118146
doi: 10.3389/fcvm.2021.813589
Nowak, A. et al. Prognostic value and link to atrial fibrillation of soluble klotho and FGF23 in hemodialysis patients. PLoS ONE 9, e100688 (2014).
pubmed: 24991914
pmcid: 4084634
doi: 10.1371/journal.pone.0100688
Takeshita, K. et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 109, 1776–1782 (2004).
pubmed: 15037532
doi: 10.1161/01.CIR.0000124224.48962.32
Hung, Y. et al. Klotho modulates pro-fibrotic activities in human atrial fibroblasts through inhibition of phospholipase C signaling and suppression of store-operated calcium entry. Biomedicines https://doi.org/10.3390/biomedicines10071574 (2022).
doi: 10.3390/biomedicines10071574
pubmed: 36551964
pmcid: 9687769
Leifheit-Nestler, M. et al. Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Nephrol. Dial. Transpl. 32, 1493–1503 (2017).
doi: 10.1093/ndt/gfw454
Slavic, S. et al. Genetic ablation of Fgf23 or klotho does not modulate experimental heart hypertrophy induced by pressure overload. Sci. Rep. 7, 11298 (2017).
pubmed: 28900153
pmcid: 5595838
doi: 10.1038/s41598-017-10140-4
Andersen, I. A., Huntley, B. K., Sandberg, S. S., Heublein, D. M. & Burnett, J. C. Jr. Elevation of circulating but not myocardial FGF23 in human acute decompensated heart failure. Nephrol. Dial. Transpl. 31, 767–772 (2016).
doi: 10.1093/ndt/gfv398
Poelzl, G. et al. Klotho is upregulated in human cardiomyopathy independently of circulating klotho levels. Sci. Rep. 8, 8429 (2018).
pubmed: 29849175
pmcid: 5976633
doi: 10.1038/s41598-018-26539-6
Corsetti, G. et al. Decreased expression of klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease. J. Geriatr. Cardiol. 13, 701–711 (2016).
pubmed: 27781061
pmcid: 5067432
Scialla, J. J. et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int. 83, 1159–1168 (2013).
pubmed: 23389416
pmcid: 3672330
doi: 10.1038/ki.2013.3
Linefsky, J. P. et al. Association of serum phosphate levels with aortic valve sclerosis and annular calcification: the cardiovascular health study. J. Am. Coll. Cardiol. 58, 291–297 (2011).
pubmed: 21737022
pmcid: 3147295
doi: 10.1016/j.jacc.2010.11.073
Campos-Obando, N. et al. Genetic evidence for a causal role of serum phosphate in coronary artery calcification: the Rotterdam study. J. Am. Heart Assoc. 11, e023024 (2022).
pubmed: 35904204
pmcid: 9375490
doi: 10.1161/JAHA.121.023024
Tentori, F. et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am. J. Kidney Dis. 52, 519–530 (2008).
pubmed: 18514987
doi: 10.1053/j.ajkd.2008.03.020
Block, G. A., Hulbert-Shearon, T. E., Levin, N. W. & Port, F. K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis. 31, 607–617 (1998).
pubmed: 9531176
doi: 10.1053/ajkd.1998.v31.pm9531176
Palmer, S. C. et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. J. Am. Med. Assoc. 305, 1119–1127 (2011).
doi: 10.1001/jama.2011.308
Teng, M. et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J. Am. Soc. Nephrol. 16, 1115–1125 (2005).
pubmed: 15728786
doi: 10.1681/ASN.2004070573
Investigators, J. D. et al. Effect of oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism receiving maintenance hemodialysis: the J-DAVID randomized clinical trial. J. Am. Med. Assoc. 320, 2325–2334 (2018).
doi: 10.1001/jama.2018.17749
Thadhani, R. et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. J. Am. Med. Assoc. 307, 674–684 (2012).
doi: 10.1001/jama.2012.120
Yoon, J. et al. Physiologic regulation of systemic klotho levels by renal CaSR signaling in response to CaSR ligands and pH
pubmed: 34551996
pmcid: 8638396
doi: 10.1681/ASN.2021020276
Komaba, H. et al. Effects of cinacalcet treatment on serum soluble klotho levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol. Dial. Transpl. 27, 1967–1969 (2012).
doi: 10.1093/ndt/gfr645
Investigators, E. T. et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N. Engl. J. Med. 367, 2482–2494 (2012).
doi: 10.1056/NEJMoa1205624
Wolf, M. et al. Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis. Clin. Kidney J. 13, 75–84 (2020).
pubmed: 32082556
doi: 10.1093/ckj/sfz034
Isakova, T. et al. Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD. J. Am. Soc. Nephrol. 26, 2328–2339 (2015).
pubmed: 25967123
pmcid: 4587706
doi: 10.1681/ASN.2015020117
Ferrari, S. L., Bonjour, J. P. & Rizzoli, R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J. Clin. Endocrinol. Metab. 90, 1519–1524 (2005).
pubmed: 15613425
doi: 10.1210/jc.2004-1039
Gutierrez, O. M. et al. Impact of phosphorus-based food additives on bone and mineral metabolism. J. Clin. Endocrinol. Metab. 100, 4264–4271 (2015).
pubmed: 26323022
pmcid: 4702463
doi: 10.1210/jc.2015-2279
Moe, S. M. et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 257–264 (2011).
pubmed: 21183586
pmcid: 3052214
doi: 10.2215/CJN.05040610
Chang, Y. M. et al. Effects of lanthanum carbonate and calcium carbonate on fibroblast growth factor 23 and hepcidin levels in chronic hemodialysis patients. Clin. Exp. Nephrol. 21, 908–916 (2017).
pubmed: 27928636
doi: 10.1007/s10157-016-1362-9
Block, G. A. et al. Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses. Nephrol. Dial. Transpl. 34, 1115–1124 (2019).
doi: 10.1093/ndt/gfy318
Ix, J. H. et al. Effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor-23 in CKD: the COMBINE trial. J. Am. Soc. Nephrol. 30, 1096–1108 (2019).
pubmed: 31085679
pmcid: 6551774
doi: 10.1681/ASN.2018101058
Block, G. A. et al. The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia. Nephrol. Dial. Transpl. 34, 339–346 (2019).
doi: 10.1093/ndt/gfy061
Pergola, P. E., Rosenbaum, D. P., Yang, Y. & Chertow, G. M. A randomized trial of tenapanor and phosphate binders as a dual-mechanism treatment for hyperphosphatemia in patients on maintenance dialysis (AMPLIFY). J. Am. Soc. Nephrol. 32, 1465–1473 (2021).
pubmed: 33766811
pmcid: 8259655
doi: 10.1681/ASN.2020101398
Kawabata, C. et al. Changes in fibroblast growth factor 23 and soluble klotho levels after hemodialysis initiation. Kidney Med. 2, 59–67 (2020).
pubmed: 33015612
doi: 10.1016/j.xkme.2019.09.007
Huang, S. H. et al. The kinetics of cystatin C removal by hemodialysis. Am. J. Kidney Dis. 65, 174–175 (2015).
pubmed: 25282341
doi: 10.1053/j.ajkd.2014.08.010
Isakova, T. et al. Fibroblast growth factor 23 in patients undergoing peritoneal dialysis. Clin. J. Am. Soc. Nephrol. 6, 2688–2695 (2011).
pubmed: 21903990
pmcid: 3206004
doi: 10.2215/CJN.04290511
Hasegawa, H. et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int. 78, 975–980 (2010).
pubmed: 20844473
doi: 10.1038/ki.2010.313
Liu, Y. et al. Novel regulatory factors and small-molecule inhibitors of FGFR4 in cancer. Front. Pharmacol. 12, 633453 (2021).
pubmed: 33981224
pmcid: 8107720
doi: 10.3389/fphar.2021.633453
Yu, C., Wang, F., Jin, C., Huang, X. & McKeehan, W. L. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J. Biol. Chem. 280, 17707–17714 (2005).
pubmed: 15750181
doi: 10.1074/jbc.M411771200
Wang, Y. & Sun, Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 54, 810–817 (2009).
pubmed: 19635988
doi: 10.1161/HYPERTENSIONAHA.109.134320
Lin, W. et al. Klotho restoration via acetylation of peroxisome proliferation-activated receptor γ reduces the progression of chronic kidney disease. Kidney Int. 92, 669–679 (2017).
pubmed: 28416226
doi: 10.1016/j.kint.2017.02.023
Zhang, Q., Yin, S., Liu, L., Liu, Z. & Cao, W. Rhein reversal of DNA hypermethylation-associated klotho suppression ameliorates renal fibrosis in mice. Sci. Rep. 6, 34597 (2016).
pubmed: 27703201
pmcid: 5050540
doi: 10.1038/srep34597
Murray, S. L. & Wolf, M. Pivoting from PTH to FGF23 to mend breaking hearts on dialysis. Circ. Res. 128, 1626–1628 (2021).
pubmed: 34043423
doi: 10.1161/CIRCRESAHA.121.319306
Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).
pubmed: 11565518
doi: 10.1056/NEJMoa011161
Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl. J. Med. 383, 2219–2229 (2020).
pubmed: 33264825
doi: 10.1056/NEJMoa2025845
The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 388, 117–127 (2023).
doi: 10.1056/NEJMoa2204233