Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue

Mencke, Rik; Harms, Geert; Mirković, Katarina; Struik, Joyce; Ark, Joris van; Loon, Ellen Van; Verkaik, Melissa; Borst, Martin H. de; Zeebregts, Clark J.; Hoenderop, Joost G. J.; Vervloet, Marc G.; Hillebrands, Jan-Luuk

doi:10.1093/cvr/cvv187

Cited by 45 publications

(30 citation statements)

References 55 publications

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“…In contrast, using real-time RT-PCR, with primers targeting different coding regions and various immune-detection techniques using several anti-α-klotho antibodies, Mencke et al . did not identify expression of α-klotho expression in the aorta of healthy individuals or in patients with CKD 57 , which is consistent with our results. Considering that expression of FGF-r3, a co-receptor for α-klotho, did not change, the likelihood that α-klotho is present in the walls of vessels and plays a role in resisting VC formation is moderate-to-low.…”

Section: Discussionsupporting

confidence: 90%

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Development of a novel chronic kidney disease mouse model to evaluate the progression of hyperphosphatemia and associated mineral bone disease

Tani

Orimo

Shimizu

et al. 2017

Sci Rep

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Medial arterial calcification (MAC) and renal osteodystrophy are complications of mineral bone disease (MBD) associated with chronic kidney disease (CKD). Our aim was to develop a novel mouse model to investigate the clinical course of CKD-MBD. Eight-week-old C57BL/6 J male mice were assigned to the following groups: the control group, fed a standard chow for 6 or 12 weeks; the CKD-normal phosphorus (NP) group, fed a chow containing 0.2% adenine, with normal (0.8%) phosphorus, for 6 or 12 weeks; and the CKD-high phosphorus (HP) group, fed 6 weeks with the 0.2% adenine/0.8% phosphorus diet, followed by a chow with 1.8% phosphorus for 2 weeks, 4 weeks or 6 weeks. Serum phosphorus was significantly increased in the CKD-HP group, and associated with MAC formation; the volume of calcification increased with longer exposure to the high phosphorus feed. MAC was associated with upregulated expression of runt-related transcription factor 2, alkaline phosphatase, and osteopontin, indicative of osteoblastic trans-differentiation of vascular smooth muscle cells. A significant mineral density depletion of cortical bone was observed. We describe the feasibility of developing a model of CKD-MBD and provide findings of a direct association between elevated serum phosphorus and the formation of MAC and renal osteodystrophy.

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Section: Discussionsupporting

confidence: 90%

“…Considering that expression of FGF-r3, a co-receptor for α-klotho, did not change, the likelihood that α-klotho is present in the walls of vessels and plays a role in resisting VC formation is moderate-to-low. This, however, does not deny the possibility that circulating α-klotho may serve as a humoral factor to protect against MAC 57 .…”

Section: Discussionmentioning

confidence: 96%

Development of a novel chronic kidney disease mouse model to evaluate the progression of hyperphosphatemia and associated mineral bone disease

Tani

Orimo

Shimizu

et al. 2017

Sci Rep

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“…Likewise, no α-Klotho or FGF23 mRNA was found in human aortic SMCs [60]. Table 2 also shows a number of other studies that failed to find α-Klotho expression in vascular SMCs or tissues [60,61,64,69,73–77]. On the other hand, there are almost an equal number of studies where α-Klotho was detected in vascular tissues or SMCs [62–64,78–86,88,89] (Table 2).…”

Section: Roles Of Klotho In Vcmentioning

confidence: 99%

Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Yamada

Giachelli

2017

Bone

256

196

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Vascular calcification (VC) is highly prevalent in aging, diabetes mellitus, and chronic kidney disease (CKD). VC is a strong predictor of cardiovascular morbidity and mortality in the CKD population. Complex pathological mechanisms are involved in the development of VC, including osteochondrogenic differentiation and apoptosis of vascular smooth muscle cells, instability and release of extracellular vesicles loaded calcium and phosphate, and elastin degradation. Elevated serum phosphate is a late manifestation of CKD, and has been shown to accelerate mineral deposition in both the vessel wall and heart valves. α-Klotho and fibroblast growth factor 23 (FGF23) are emerging factors in CKD-mineral and bone disorder (CKD-MBD) and are thought to be involved in the pathogenesis of uremic VC. There are discordant reports regarding the biomedical effects of FGF23 on VC. In contrast, mounting evidence supports a well-supported protective role for α-Klotho on VC. Further studies are warranted to elucidate potential roles of FGF23 and α-Klotho in VC and to determine where and how they are synthesized in normal and disease conditions. A thorough systemic evaluation of the biomedical interplay of phosphate, FGF23, and α-Klotho may potentially lead to new therapeutic options for patients with CKD-MBD.

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“…The present results clearly established that the Klotho gene is not expressed in the rat aorta. Some studies have indicated the presence of Klotho mRNA and protein in VSMCs with either decreased or increased expression in uremia, and some have found that Klotho was induced in the adventitia of the uremic rat aorta (17,29,37,48), whereas other investigations found no signs of Klotho being expressed in the aorta (35). The RT-PCR method used for the detection of Klotho mRNA might be too sensitive for the relevant demonstration of Klotho, as shown in the results of the present study, and factors related to poor specificity and sensitivity of the available Klotho antibodies for protein detection may all critically account for the discrepant findings in the actual literature, as recently discussed by our group (27).…”

Section: Uremicmentioning

confidence: 99%

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

Rukov

Gravesen

Mace

et al. 2016

American Journal of Physiology-Renal Physiology

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Rukov JL, Gravesen E, Mace ML, Hofman-Bang J, Vinther J, Andersen CB, Lewin E, Olgaard K. Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing. Am J Physiol Renal Physiol 310: F477-F491, 2016. First published January 6, 2016 doi:10.1152/ajprenal.00472.2015.-The development of vascular calcification (VC) in chronic uremia (CU) is a tightly regulated process controlled by factors promoting and inhibiting mineralization. Next-generation high-throughput RNA sequencing (RNA-seq) is a powerful and sensitive tool for quantitative gene expression profiling and the detection of differentially expressed genes. In the present study, we, for the first time, used RNA-seq to examine rat aorta transcriptomes from CU rats compared with control rats. Severe VC was induced in CU rats, which lead to extensive changes in the transcriptional profile. Among the 10,153 genes with an expression level of Ͼ1 reads/kilobase transcript/million mapped reads, 2,663 genes were differentially expressed with 47% upregulated genes and 53% downregulated genes in uremic rats. Significantly deregulated genes were enriched for ontologies related to the extracellular matrix, response to wounding, organic substance, and ossification. The individually affected genes were of relevance to osteogenic transformation, tissue calcification, and Wnt modulation. Downregulation of the Klotho gene in uremia is believed to be involved in the development of VC, but it is debated whether the effect is caused by circulating Klotho only or if Klotho is produced locally in the vasculature. We found that Klotho was neither expressed in the normal aorta nor calcified aorta by RNA-seq. In conclusion, we demonstrated extensive changes in the transcriptional profile of the uremic calcified aorta, which were consistent with a shift in phenotype from vascular tissue toward an osteochondrocytic transcriptome profile. Moreover, neither the normal vasculature nor calcified vasculature in CU expresses Klotho.

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Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue

Abstract: Using several independent and validated methods, we conclude that full-length, membrane-bound Klotho is not expressed in healthy or uraemic human vascular tissue.

Cited by 45 publications

References 55 publications

Development of a novel chronic kidney disease mouse model to evaluate the progression of hyperphosphatemia and associated mineral bone disease

Development of a novel chronic kidney disease mouse model to evaluate the progression of hyperphosphatemia and associated mineral bone disease

Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho

Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing

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