The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology

Mencke, Rik; Hillebrands, Jan Luuk

doi:10.1016/j.arr.2016.09.001

Cited by 91 publications

(59 citation statements)

References 176 publications

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“…In the murine model, it now has been demonstrated that Klotho deficiency can cause vascular calcification, endothelial dysfunction, cardiac dysfunction, and cardiomyopathy by promoting oxidative stress, inflammation, apoptosis, and damage of cardiomyocytes [27]. Furthermore, Klotho deficiency can lead to cardiac hypertrophy and remodeling through oxidative stress and other mechanisms [28], while Klotho treatment can reverse the above processes [29]. And it has been shown that endogenous Klotho can prevent cardiac hypertrophy and fibrosis in mice [15].…”

Section: Discussionmentioning

confidence: 99%

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Yang

et al. 2020

Cardiorenal Med

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Background: Experimental studies indicate that Klotho deficiency is a pathogenic factor for CKD-related complications, including cardiovascular disease (CVD). However, the association between serum Klotho and clinical outcomes in nondiabetic CKD patients needs to be further clarified. We aimed to determine whether serum Klotho levels are associated with CVD events and mortality in predialysis CKD patients without diabetes. Methods: A total of 336 CKD stage 2-5 predialysis patients without diabetes were recruited and followed from the end of 2014 to January 2019 for CVD events and overall mortality. Serum Klotho was detected by ELISA and divided into quartiles (lowest, middle, second highest, and highest quartiles) according to their serum Klotho category. Results: After a median follow-up of 3.52 years (IQR 3.34-3.76), Kaplan-Meier analysis showed that, compared to participants with a Klotho level in the highest quartile (the reference category), those in the lowest Klotho quartile were associated with a higher all-cause mortality risk (HR = 7.05; 95% CI 1.59-31.25) and a higher CVD event risk (HR = 3.02; 95% CI 1.45-6.30). In addition, the middle Klotho quartile was also associated with CVD event risk (HR = 2.56; 95% CI 1.21-5.41). Moreover, in the multivariate-adjusted model, the lowest Klotho quartile remained significantly associated with all-cause mortality (HR = 5.17; 95% CI 1.07-24.96), and the middle Klotho quartile maintained a significant association with CVD event risk (HR = 2.32; 95% CI 1.03-5.21). Conclusion: These results suggest that lower serum Klotho levels are independently associated with overall mortality and CVD events in nondiabetic predialysis CKD patients.

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Section: Discussionmentioning

confidence: 99%

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Yang

et al. 2020

Cardiorenal Med

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“…Conversely, over-expression of Kl in mice protects against cardiovascular disease. In addition, Kl is involved in the regulation of several pathways, including VEGF and Wnt (30). However, considering the evidence reviewed above and that these three genes present a lower fraction of singleton predicted deleterious missense variants compared to NOTCH1 , caution is needed when considering these genes as candidates for CHD/TOF.…”

Section: Discussionmentioning

confidence: 99%

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Manshaei

Merico

Reuter

et al. 2020

Preprint

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Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD).To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF or related CHD. We adapted a burden test originally developed for de novo variants to assess singleton variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets, and for multiple testing.The gene burden test identified a significant burden of deleterious missense variants in NOTCH1 (Bonferroni-corrected p-value <0.01). These NOTCH1 variants showed significant enrichment for those affecting the extracellular domain, and especially for disruption of cysteine residues forming disulfide bonds (OR 39.8 vs gnomAD). Individuals with NOTCH1 variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in TOF had more modest statistical support and singleton missense variant results were non-significant for gene-set burden. For singleton truncating variants, the gene burden test confirmed significant burden in FLT4. Gene-set burden tests identified a cluster of pathways corresponding to VEGF signaling (FDR=0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR=0.8%), that suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Analyses using unrelated sequencing datasets supported specificity of the findings for CHD.The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.Author summaryWe analyzed the ultra-rare nonsynonymous variant burden for genome sequencing data from 231 individuals with congenital heart defects, most with tetralogy of Fallot. We adapted a burden test originally developed for de novo variants. In line with other studies, we identified a significant truncating variant burden for FLT4 and deleterious missense burden for NOTCH1, both passing a stringent Bonferroni multiple-test correction. For NOTCH1, we observed frequent disruption of cysteine residues establishing disulfide bonds in the extracellular domain. We also identified genes with BH-FDR <10% that were not previously implicated. To overcome limited power for individual genes, we tested gene-sets corresponding to functional pathways and mouse phenotypes. Gene-set burden of truncating variants was significant for vascular endothelial growth factor signaling and abnormal vasculature phenotypes. These results confirmed previous findings and suggested additional candidate genes for experimental validation in future studies. This methodology can be extended to other case-only sequencing data in which ultra-rare variants make a substantial contribution to genetic etiology.

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“…Renal Klotho deficiency is clearly found in AKI induced by I/R injury (Hu et al, ). Klotho deficiency causes a number of vascular phenotypes, including endothelial dysfunction and impaired angiogenesis and vasculogenesis (Mencke & Hillebrands, ). With regard to the vasculature, Klotho has many protective effects and its overexpression could ameliorate endothelial dysfunction by suppressing expression of adhesion molecules in the endothelium (Mencke & Hillebrands, ).…”

Section: Discussionmentioning

confidence: 99%

“…Klotho deficiency causes a number of vascular phenotypes, including endothelial dysfunction and impaired angiogenesis and vasculogenesis (Mencke & Hillebrands, ). With regard to the vasculature, Klotho has many protective effects and its overexpression could ameliorate endothelial dysfunction by suppressing expression of adhesion molecules in the endothelium (Mencke & Hillebrands, ). Moreover, increasing Klotho levels could resist against induction of renal disease (Guan et al, ; Hu et al, ; Panesso et al, ; Shi et al, ; Sugiura et al, ; Zhou et al, ).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Salvianolic acid A on ischaemia‐reperfusion acute kidney injury in rats through protecting against peritubular capillary endothelium damages

Zhang

Dong

Wang

et al. 2017

Phytotherapy Research

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Renal ischaemia‐reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Peritubular capillary (PTC) endothelium damages are an important pathogenesis during I/R AKI. Salvianolic acid A (SAA) possesses various pharmacological activities. The study investigated whether SAA ameliorated I/R AKI through protecting against PTC endothelium damages. Male Sprague–Dawley rats were divided into 6 groups: control, sham, I/R, and I/R plus SAA (2.5, 5, 10 mg/kg) groups. Rats were subjected to bilateral renal pedicle clamping for 60 min, and killed at 24 hr after reperfusion. Kidney injury, PTC endothelium damages and factors affecting PTC endothelium were evaluated. SAA significantly decreased blood urea nitrogen and serum creatinine levels, and reduced urine kidney injury molecule‐1 concentration. Simultaneously, SAA alleviated histological damages, prevented PTC endothelium damages, preserved the density of PTC and improved renal hypoxia. Furthermore, SAA inhibited platelet activation, elevated Klotho protein expression and up‐regulated vascular endothelial growth factor A expression. Overall, SAA has protective effects on AKI induced by I/R. Preventing PTC endothelium damages and preserving PTC integrity to improve the renal hypoxia may be the ways for SAA to ameliorate AKI. All these indicate that SAA is likely to be a promising agent for AKI.

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The role of the anti-ageing protein Klotho in vascular physiology and pathophysiology

Cited by 91 publications

References 176 publications

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Serum Klotho, Cardiovascular Events, and Mortality in Nondiabetic Chronic Kidney Disease

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Protective effect of Salvianolic acid A on ischaemia‐reperfusion acute kidney injury in rats through protecting against peritubular capillary endothelium damages

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