Calcium and Klotho: the secret of immortality?

Clinical relevance
The life expectancy of humans is continuously rising and consequently ageing-related disorders increasingly
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challenge the quality of life of the elderly. Ageing is tightly associated with a negative calcium (Ca ) balance leading
to among others osteoporosis, arteriosclerosis and ectopic calcification. Recently, klotho (named after the Greek
goddess who spins the thread of life) was identified as new anti-ageing hormone being instrumental in the
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process of age- related adaptations in the Ca balance.
Background
Klotho is a type I membrane glycoprotein which shares homology to -glucosidase enzymes. Interestingly, klotho
gene ablation in mice resulted in a syndrome closely resembling human ageing, including short life span, bone
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aberrations, skin atrophy and a disturbed Ca balance together with high serum vitamin D levels. In addition,
polymorphisms in the klotho gene have been linked to reduced bone mineral density in humans. However, the
molecular function of klotho and the down-stream targets of this anti- ageing hormone remain to be identified.
Recently, we showed that klotho is predominantly expressed in kidney, where it is secreted in the pro-urine.
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Furthermore, we demonstrated that the epithelial Ca channel (TRPV5), which is the gate-keeper in the process of
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Ca active reabsorption, is stimulated by klotho via a novel extracellular activation mechanism. We hypothesize
that klotho hydrolyses via its -glucuronidase activity the extracellular TRPV5 sugar residues, entrapping the
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channel in the plasma membrane to maintain durable Ca transport activity.
Goals
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The general aim of this project is to delineate in detail the function of klotho in the regulation of the Ca balance
providing new insights into the molecular mechanism of ageing. To this end the following key objectives will be
addressed:
i) Molecular mechanism of klotho-mediated TRPV5 channel activation. We will investigate the modification of the
extracellular sugar residues of TRPV5 by klotho, the molecular identity of the klotho-mediated signaling cascade
and finally the effect of klotho on the plasma membrane recycling process of TRPV5.
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ii) The in vivo function of klotho on renal Ca handling. The mechanism and hormonal regulation of the klotho
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secretion into the pro-urine will be studied in animal models. Subsequently, the action of klotho on TRPV5, Ca
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reabsorption and ultimately Ca balance will be investigated.
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iii) Functional correlation of klotho and Ca homeostasis in humans during ageing. The association between the
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urinary klotho expression and the Ca balance during ageing will be determined in subjects of The Nijmegen
Biomedical Study. Subsequently, the functional consequences of the recently identified non-synonymous SNPs in
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klotho on the Ca balance and TRPV5 channel activity will be studied.
We offer:
The possibility to perform and present high-quality clinically-oriented research in a professional, multicultural and
highly-motivating working environment with about 35 colleagues in a well-equipped department. The student will
learn how to perform basic molecular biology techniques including cloning, quatitative real-time PCR analysis,
patient DNA sequencing, immunohistochemistry, confocal laser scanning microscopy and various biochemical
assays including blood ion determinations.
Contact:
Department:
Contact person:
Telephone number:
Email address:
Website:

Physiology
Tim Schreuder
0243614222
tim.schreuder@radboudumc.nl
www.physiomics.eu