Reduced Klotho is associated with the presence and severity of coronary artery disease

Navarro‐González, Juan F.; Donate-Correa, Javier; Fuentes, Mireya; Pérez-Hernández, Horacio; Martínez‐Sanz, Rafael; Mora‐Fernández, Carmen

doi:10.1136/heartjnl-2013-304746

Cited by 138 publications

(128 citation statements)

References 47 publications

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“…Recently, some studies have reported that Klotho deficiency might contribute to the development of atherosclerosis and atherothrombosis. [50][51][52] In our study, we showed that exogenous Klotho administration not only significantly attenuated IS-induced thrombosis, but also retarded the acceleration of atherosclerosis in apoE 2/2 mice with CKD. There are multiple targets of Klotho.…”

Section: Discussionsupporting

confidence: 52%

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

Yang

Du²,

Wang³

et al. 2017

Blood

122

119

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Key Points• Uremic solute IS increases platelet activity via activation of ROS/p38MAPK signaling.• Klotho counteracts ISinduced thrombosis by restraining platelet hyperactivity.Thrombosis is a common complication of chronic kidney disease (CKD), but the causes and mechanisms of CKD-associated thrombosis are not well clarified. Here, we show that platelet activity is remarkably enhanced in CKD mice, with increase of serum indoxyl sulfate (IS), a typical uremic toxin, which cannot be effectively cleared by routine dialysis. Ex vivo and in vitro experiments reveal that IS displays a distinct ability to enhance platelet activities, including elevated response to collagen and thrombin, increases in plateletderived microparticles, and platelet-monocyte aggregates. The flow chamber assay and carotid artery thrombosis model demonstrate that IS-induced platelet hyperactivity contributes to thrombus formation. Further investigations disclose that reactive oxygen species (ROS)-mediated p38MAPK signaling plays a key role in IS-induced platelet hyperactivity. Moreover, we show that Klotho, which is expressed dominantly in the kidneys, has the capacity to counteract IS-induced platelet hyperactivity by inhibiting ROS/p38MAPK signaling, whereas Klotho reduction may aggravate the effect of IS on platelet activation in CKD and klotho 1/2 mice. Finally, we demonstrate that Klotho protein treatment can protect against IS-induced thrombosis and atherosclerosis in apoE 2/2 mice. Our findings uncover the mechanism of platelet hyperactivity induced by IS and provide new insights into the pathogenesis and treatment of CKD-associated thrombosis.

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Section: Discussionsupporting

confidence: 52%

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

Yang

Du²,

Wang³

et al. 2017

Blood

122

119

View full text Add to dashboard Cite

show abstract

“…Indeed, α‐Klotho deficiency in mice leads to a limited vasodilatory response and increased permeability in the endothelial cells among other vascular complications also observed in CKD patients 22, 23, 24, 41. As reported previously in other uremic in vivo models20, 21 and CKD patients,42, 43 we confirmed that impaired kidney function induced downregulation of mRNA and α‐Klotho protein levels in kidney tissue accompanied by lower serum concentrations.…”

Section: Discussionsupporting

confidence: 89%

“…α‐Klotho is an antiaging protein, and its deficiency is associated with a cardiovascular phenotype including arteriosclerosis, vascular calcification, and, importantly, endothelial cell dysfunction 22, 23. In humans, deficiency in serum α‐Klotho correlates with cardiovascular complications 24. However, a direct role of serum α‐Klotho deficiency on endothelial dysfunction in patients with CKD has not been established.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

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“…First, the study sample was relatively small. Second, it has been reported that FGF23 level may be higher among subjects with incident myocardial infarction 39) and patients with significant CAD present lower soluble concentrations of Klotho 40) . The current study population underwent chest MDCT under the clinical diagnosis or suspicion of coronary artery disease; therefore, our findings may not be applicable to the general population.…”

Section: Logistic Regression Analysis For the Association Between -Klmentioning

confidence: 99%

Gender Specific Association between Serum Fibroblast Growth Factor 23/α-Klotho and Coronary Artery and Aortic Valve Calcification

Morita

Takeda

Fujita

et al. 2015

J Atheroscler Thromb

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Aim: Fibroblast growth factor 23 (FGF23) and -Klotho have been recently identified to play a crucial role in calcium/phosphate metabolism. We herein investigated the possible relation between serum FGF23/ -Klotho levels and coronary artery calcification (CAC) and aortic valve calcification (AVC). Methods: Among subjects with diagnosed or suspected coronary artery disease (CAD), CAC and AVC were estimated via the Agatston score of 320-detector computed tomography images, and serum FGF23 and -Klotho levels were measured. Results: In total, 157 subjects were enrolled (75 women and 82 men). We performed logistic regression using CAC as a dependent variable; the highest FGF23 tertile ( 52.5 pg/mL) was significantly positively associated with CAC with an odds ratio of 6.61 versus the lowest FGF23 tertile ( 35.3 pg/mL) in women after the adjustment for potential confounding variables including age, renal function, hypertension, statin use, diuretic use, and calcium/phosphate metabolism related factors. In addition, the highest -Klotho tertile ( 561 pg/mL) was significantly associated with AVC with an odds ratio of 6.31 versus the lowest -Klotho tertile ( 306 pg/mL) in men after adjusting for the same variables. On the other hand, the association between FGF23 and CAC/AVC in men or that between -Klotho and CAC/AVC in women was nonsignificant. Conclusion: Among subjects with diagnosed or suspected CAD, serum FGF23 was positively associated with CAC in women and serum -Klotho was positively associated with AVC in men independent of the confounding variables, including the renal function and calcium/phosphate metabolismrelated factors. J Atheroscler Thromb, 2015; 22: 1338-1346.

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Reduced Klotho is associated with the presence and severity of coronary artery disease

Cited by 138 publications

References 47 publications

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease–associated thrombosis in mice

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Gender Specific Association between Serum Fibroblast Growth Factor 23/α-Klotho and Coronary Artery and Aortic Valve Calcification

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