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Klotho, a Gene Related to a Syndrome Resembling Human Premature Aging, Functions in a Negative Regulatory Circuit of Vitamin D Endocrine System

Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto 606-8507, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: Yo-ichi Nabeshima, Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. E-mail: nabemr{at}lmls.med.kyoto-u.ac.jp.

The klotho gene encodes a novel type I membrane protein of ß-glycosidase family and is expressed principally in distal tubule cells of the kidney and choroid plexus in the brain. These mutants displayed abnormal calcium and phosphorus homeostasis together with increased serum 1,25-(OH)₂D. In kl^-/- mice at the age of 3 wk, elevated levels of serum calcium (10.9 ± 0.31 mg/dl vs. 10.0 ± 0.048 mg/dl in wild-type mice), phosphorus (14.7 ± 1.1 mg/dl vs. 9.7 ± 1.5 mg/dl in wild type) and most notably, 1,25-(OH)₂D (403 ± 99.7 mg/dl vs. 88.0 ± 34.0 mg/dl in wild type) were observed.

Reduction of serum 1,25-(OH)₂D concentrations by dietary restriction resulted in alleviation of most of the phenotypes, suggesting that they are downstream events resulting from elevated 1,25-(OH)₂D. We searched for the signals that lead to up-regulation of vitamin D activating enzymes. We examined the response of 1-hydroxylase gene expression to calcium regulating hormones, such as PTH, calcitonin, and 1,25-(OH)₂D₃. These pathways were intact in klotho null mutant mice, suggesting the existence of alternate regulatory circuits. We also found that the administration of 1,25-(OH)₂D₃ induced the expression of klotho in the kidney. These observations suggest that klotho may participate in a negative regulatory circuit of the vitamin D endocrine system, through the regulation of 1-hydroxylase gene expression.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR

Ligands:   Calcitriol

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