Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

Lim, Kenneth; Lu, Tzongshi; Molostvov, Guerman; Lee, Christina; Lam, F.T.; Zehnder, Daniel; Hsiao, Li‐Li

doi:10.1161/circulationaha.111.053405

Cited by 396 publications

(423 citation statements)

References 57 publications

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“…It remains unknown how far circulating sKlotho levels reflect tissue Klotho expression. In the context of controversial data on Klotho expression in vascular cells (21,22,30), we cannot rule out that Klotho tissue expression-unlike plasma sKlotho-may be associated with cardiovascular outcome. Nonetheless, following most recent animal data, which argue against Klotho expression in vascular cells (30), most experts believe that Klotho tissue expression is largely confined to kidney and parathyroidal cells.…”

Section: Discussionmentioning

confidence: 93%

“…More direct evidence for a beneficial cardiovascular role of sKlotho derives from rodent CKD models, in which sKlotho lowered active phosphate uptake by vascular smooth muscle cells and thus protected animals against vascular calcification (21). Similarly, in human aortic smooth muscle cells, uremic serum downregulated Klotho gene expression and induced calcifying pathways, whereas restoration of Klotho activity protected against extracellular calcium deposition (22).…”

Section: Discussionmentioning

confidence: 99%

“…The latter is derived from either cleavage of Klotho from the cell membrane or alternative splicing. Several renoprotective (18)(19)(20) and vasculoprotective (21,22) effects have been ascribed to sKlotho. With the recent establishment of an ELISA (23), sKlotho may become another CKD-MBD biomarker.…”

Section: Introductionmentioning

confidence: 99%

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Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Seiler

Rogačev

Roth

et al. 2014

Clinical Journal of the American Society of Nephrology

129

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Background and objectives CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.Design, settings, participants, & measurements Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.Results Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).Conclusions In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Seiler

Rogačev

Roth

et al. 2014

Clinical Journal of the American Society of Nephrology

129

View full text Add to dashboard Cite

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“…It is possible that, in the absence of klotho, increased FGF23 levels exert pro-calcific effects via non-specific low affinity binding to its receptors [17]. A recent study showed that in human arteries, restoration of klotho expression by vitamin D receptor activators could unmask anticalcific effect of FGF23 [18]. These data, even if showing a strong and independent association between FGF23, CVD and hard end points throughout different stages of CKD, are still insufficient to determine the nature of FGF23 as a biomarker or as an effector in vascular calcifications.…”

Section: Discussionmentioning

confidence: 99%

Plasma Fibroblast Growth Factor-23 Level and its Relation to Carotid Artery Atherosclerosis in Hemodialysis Patients

Ghonemy¹

2017

UNOAJ

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Background: Abnormalities in bone metabolism are a prevalent condition in CKD patients. FGF23 has been suggested to play a role in vascular calcification in patients on regular hemodialysis (HD).Objective: This work was carried out to evaluate the prevalence of carotid artery atherosclerosis in patients with end stage renal disease (ESRD) on regular haemodialysis and the role of FGF-23 in this event.Subject and methods: A total number of 50 patients aged over 18 years and on regular haemodialysis for one or more years were included in this study. Intact FGF-23 and other laboratory parameters were measured by specific methods for all patients; Also Duplex scan of the carotid arteries was performed to assess carotid intima-media thickness (CIMT) by high-resolution real-time B mode ultrasonography.Results: Serum phosphorus, CIMT, LDL, There found to be significantly high with increasing FGF 23 levels (pis 0.005, 0.001, 0.02 and 0.001 respectively). While albumin level was significantly lower with increasing FGF-23 level (p is 0.013). Levels of phosphorus, Parathyroid hormone (PTH) and CRP got significantly higher with the increase in (CIMT) (p is 0.007, 0.001 and 0.004 respectively). FGF 23 levels were significantly correlated with each of CIMT, phosphorus and PTH levels. Correlation was significant between CIMT and age of patient, blood pressure, diabetes, smoking habits, more hemodialysis duration, CRP, higher phosphorus level, FGF23 level, low serum albumin, and higher PTH level. From multiple regression analysis, the most important risk factors correlated to carotid artery atherosclerosis are FGF23, higher phosphorus level, CRP and Diabetes in the order. Conclusion:FGF23 is a risk factor for the occurrence of vascular atherosclerosis in hemodialysis patients Monitoring of the FGF23 levels may be recommended to predict the possibility of vascular atherosclerosis in those types of patients.

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“…It has recently been shown that not only FGFR1, but also FGFR3 is expressed in human vascular tissue (Donate-Correa et al, 2011; Lim et al, 2012). Furthermore, it has demonstrated that expression of FGFR1 and FGFR3 in human arteries from healthy individuals and CKD patients is critical for vascular calcification, and that the physical association of Klotho, FGFR1 and FGFR3 is an essential mechanism to prevent critical vascular calcification (Lim et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

A protective role for FGF23 in local defence against disrupted arterial wall integrity?

Zhu¹,

Mackenzie²,

Millán³

et al. 2013

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Increasing interest is focusing on the role of the FGF-23/Klotho axis in mediating vascular calcification. However, the underpinning mechanisms have yet to be fully elucidated. Murine VSMCs were cultured in calcifying medium for a 21d period. FGF-23 mRNA expression was significantly up-regulated by 7d (1.63 fold; P<0.001), with a concomitant increase in protein expression. mRNA and protein expression of both FGFR1 and Klotho were confirmed. Increased FGF-23 and Klotho protein expression was also observed in the calcified media of Enpp1 −/− mouse aortic tissue. Reduced calcium deposition was observed in calcifying VSMCs cultured with recombinant FGF-23 (10ng/ml; 28.1% decrease; P<0.01). Calcifying VSMCs treated with PD173074, an inhibitor of FGFR1 and FGFR3, showed significantly increased calcification (50nM; 87.8% increase; P<0.001). FGF-23 exposure induced phosphorylation of ERK1/2. Treatment with FGF-23 in combination with PD98059, an ERK1/2 inhibitor, significantly increased VSMC calcification (10μM; 41.3% increase; P<0.01). Use of FGF-23 may represent a novel therapeutic strategy for inhibiting vascular calcification.

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Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23

Abstract: Background-Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney.FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification.

Cited by 396 publications

References 57 publications

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Associations of FGF-23 and sKlotho with Cardiovascular Outcomes among Patients with CKD Stages 2–4

Plasma Fibroblast Growth Factor-23 Level and its Relation to Carotid Artery Atherosclerosis in Hemodialysis Patients

A protective role for FGF23 in local defence against disrupted arterial wall integrity?

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