Increased parathyroid expression of klotho in uremic rats

Hofman-Bang, Jacob; Martus, Giedre; Santini, Martin A.; Ølgaard, Klaus; Lewin, Ewa

doi:10.1038/ki.2010.215

Cited by 63 publications

(50 citation statements)

References 40 publications

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“…1,12,21 aKlotho protein expression is detected in renal tubules, 21,46 choroid plexus, 46 islet cells in pancreas, 47 and the parathyroid gland. 11,48,49 However, the high expression in the kidney does not necessarily indicate that circulating aKlotho is of renal origin. To test whether the kidney is a major source of endocrine aKlotho in mammals, we measured serum aKlotho protein in suprarenal and infrarenal vena cava of normal rats by direct puncture and human subjects who underwent right heart catheterization.…”

Section: Resultsmentioning

confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

228

254

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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Section: Resultsmentioning

confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

228

254

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“…Hence, Klotho can exert effects on distant organs by circulating as a soluble protein in body fluids including blood, urine, and cerebrospinal fluid [24,29]. Klotho transcript is highest in the kidney, but it is also expressed in the brain, parathyroid gland, heart, pancreatic β-islet cell, and placenta with lesser abundance [4,22,24,37,42,65]. The multi-organ defect observed in the Klotho-deficient (Kl −/− ) mice, including many organs that do not normally express Klotho, is compatible with the notion that Klotho functions as humoral factor exerting actions on multiple remote organs.…”

Section: The Pleiotropic Action Of Klothomentioning

confidence: 99%

Klotho: a novel regulator of calcium and phosphorus homeostasis

Huang

Moe

2011

Pflugers Arch - Eur J Physiol

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Klotho which was originally identified as an anti-aging protein is emerging as a substance with multiple effects on many systems including mineral homeostasis. In addition to its membrane-bound function as a co-receptor for fibroblast growth factor-23, soluble Klotho exerts effects as a circulating substance in plasma and urine. Novel features of this system include its autocrine-paracrine-endocrine glycan-modifying enzymatic function in the urinary lumen on calcium and phosphate transporters. Klotho induces phosphaturia by inhibiting the proximal tubule Na-coupled phosphate transporter. The action of Klotho is enzymatic in nature which includes alteration of transport activity and the more traditional means of regulation by trafficking. Klotho reduces calciuria by its distal as a sialidase directly on the apical calcium channel. Desialidation of the channel exposes glycan residues that promote binding to galectin-1, resulting in stabilization of residence on the plasma membrane. Through its systematic as well as renal actions, Klotho is emerging as a principal calciophosphoregulatory hormone.

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“…Quantitative RT-PCR was performed on a total of 22 target genes and 3 housekeeping genes (58) as previously described (12). The 22 genes were selected among those expected to be involved the osteochondrocytic transition.…”

Section: Animalsmentioning

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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Increased parathyroid expression of klotho in uremic rats

Cited by 63 publications

References 40 publications

Renal Production, Uptake, and Handling of Circulating αKlotho

Renal Production, Uptake, and Handling of Circulating αKlotho

Klotho: a novel regulator of calcium and phosphorus homeostasis

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

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