Fibroblast growth factor 23—Klotho and hypertension: experimental and clinical mechanisms

Freundlich, Michael; Gamba, Gerardo; Rodríguez‐Iturbe, Bernardo

doi:10.1007/s00467-020-04843-6

Cited by 27 publications

(24 citation statements)

References 147 publications

(231 reference statements)

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“… 4 It has been shown that FGF23 may participate in the pathogenesis of hypertension through the activation of RAAS. 5 , 6 Thus, we hypothesized that children with hypertension with higher FGF23 levels might have a better response to ACEIs. This study was designed to explore the value of plasma FGF23 in predicting the therapeutic efficacy of fosinopril in children with primary hypertension.…”

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confidence: 99%

Plasma Fibroblast Growth Factor 23 as a Predictor for Fosinopril Therapeutic Efficacy in Pediatric Primary Hypertension

Lin

Cui

Yuan

et al. 2022

JAHA

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Background Plasma fibroblast growth factor 23 (FGF23) has been reported to be a predictive biomarker for therapeutic effectiveness of angiotensin‐converting enzyme inhibitors in heart failure. Higher plasma FGF23 levels have been shown in pediatric primary hypertension, but the predictive value of FGF23 for angiotensin‐converting enzyme inhibitors’ effectiveness in pediatric primary hypertension has not been documented. Methods and Results This is a prospective study. An exploratory study with 139 patients was first conducted to determine the cutoff value of FGF23 for the prediction of treatment responsiveness. After receiving fosinopril for 4 weeks, of all 139 patients, 91 responded, while 48 did not respond to the treatment, and the responders had a significantly higher baseline plasma FGF23 level than nonresponders ( P <0.01). Multiple regression analysis revealed a significant impact of baseline plasma FGF23 levels on fosinopril responsiveness ( P <0.05). The receiver operating characteristic curve analysis showed that the plasma FGF23 predicted the effectiveness of fosinopril treatment with an area under the curve of 0.784 (95% CI, 0.704–0.863) for a sensitivity and a specificity of 67.0% and 89.6%, respectively, for a cutoff value of 62.08 RU/mL. Subsequently, another group of 40 patients were recruited for validation. The blood pressure control rate in those (n=22) with baseline plasma FGF23 >62.08 RU/mL was significantly higher than that in children (n=18) with FGF23 ≤62.08 RU/mL ( P <0.05). Conclusions Plasma FGF23 might be a valuable biomarker to guide fosinopril therapy for primary hypertension in children.

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confidence: 99%

Plasma Fibroblast Growth Factor 23 as a Predictor for Fosinopril Therapeutic Efficacy in Pediatric Primary Hypertension

Lin

Cui

Yuan

et al. 2022

JAHA

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“…Although our study has provided novel insights into the pathogenesis of hypertension in Hyp mice, a key question in this context remains unanswered: what is driving the stimulation of RAAS in aged Hyp mice? It has been suggested that FGF23 hypersecretion may stimulate the RAAS through the suppression of vitamin D hormone production in CKD [ 27 , 28 ]. However, whether RAAS is regulated by vitamin D remains a controversial issue [ 29 ], and it is currently not known if this proposed mechanism may also be relevant for Hyp mice.…”

Section: Discussionmentioning

confidence: 99%

Activation of RAAS Signaling Contributes to Hypertension in Aged Hyp Mice

et al. 2022

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High circulating levels of fibroblast growth factor-23 (FGF23) are associated with left ventricular hypertrophy as well as increased morbidity and mortality in patients suffering from chronic kidney disease. However, the mechanisms underlying this association are controversial. Here, we aimed to further characterize the cardiovascular sequelae of long term endogenous FGF23 hypersecretion using 14-month-old male Hyp mice as a model of FGF23 excess. Hyp mice were characterized by a ~10-fold increase in circulating intact FGF23, hypophosphatemia, increased serum aldosterone, but normal kidney function, relative to wildtype (WT) controls. Cardiovascular phenotyping did not reveal any evidence of left ventricular hypertrophy or functional impairment in 14-month-old Hyp mice. Fractional shortening, ejection fraction, molecular markers of hypertrophy (Anp, Bnp), and intracardiac markers of contractility and diastolic function were all unchanged in these animals. However, intraarterial catheterization revealed an increase in systolic, diastolic, and mean arterial pressure of ~12 mm Hg in aged Hyp mice relative to WT controls. Hypertension in Hyp mice was associated with increased peripheral vascular resistance. To test the hypothesis that a stimulation of the renin–angiotensin–aldosterone system (RAAS) contributes to hypertension in aged Hyp mice, we administered the angiotensin receptor blocker losartan (30 mg/kg twice daily) or the mineralocorticoid receptor antagonist canrenone (30 mg/kg once daily) to aged Hyp and WT mice over 5 days. Both drugs had minor effects on blood pressure in WT mice, but reduced blood pressure and peripheral vascular resistance in Hyp mice, suggesting that a stimulation of the RAAS contributes to hypertension in aged Hyp mice.

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“…Kidneys: Cheng et al, 2010 ; Kuro-o, 2010 , 2019 , 2021 ; Maquigussa et al, 2018 ; Oishi et al, 2021 ; Prud’homme et al, 2017a , 2020 ; Saar-Kovrov et al, 2021 ; Takenaka et al, 2017 ; Xing et al, 2021 ; Zou et al, 2018 . Cardiovascular: Chen K, et al, 2021 ; Freunlich et al, 2021 ; Manrique et al, 2016 ; Myung et al, 2022 ; Martin-Nunez et al, 2022 ; Olejnik et al, 2018 , 2020 ; Tyrenkov et al, 2021 ; Wang F and Zheng, 2022 ; Yang et al, 2015 . Brain: Dias et al, 2021 ; Driscoll et al, 2021 ; Cararo-Lopes et al, 2017 ; Fung et al, 2022 ; Hanson et al, 2021 ; Kundu et al, 2022 ; Laszczyk et al, 2017 ; Mytych, 2022 ; Nietzel et al, 2021; Sanz et al, 2021 .…”

Section: Klotho and Neurodegenerative Diseasesunclassified

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Fibroblast growth factor 23—Klotho and hypertension: experimental and clinical mechanisms

Cited by 27 publications

References 147 publications

Plasma Fibroblast Growth Factor 23 as a Predictor for Fosinopril Therapeutic Efficacy in Pediatric Primary Hypertension

Plasma Fibroblast Growth Factor 23 as a Predictor for Fosinopril Therapeutic Efficacy in Pediatric Primary Hypertension

Activation of RAAS Signaling Contributes to Hypertension in Aged Hyp Mice

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

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