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NDT Advance Access published online on June 24, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl335
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 3, 2005
Accepted May 15, 2006

Original Article

Defect in parathyroid-hormone-induced luminal calcium absorption in connecting tubules of Klotho mice

Shuichi Tsuruoka 1 *, Kenta Nishiki 1, Takashi Ioka 1, Hitoshi Ando 1, Yuichiro Saito 2, Masahiko Kurabayashi 2, Ryozo Nagai 3, and Akio Fujimura 1

1 Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, Japan
2 Second Department of Internal Medicine, Gumma University School of Medicine, Gumma, Japan
3 Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed.
Shuichi Tsuruoka, E-mail: tsuru{at}jichi.ac.jp



  Abstract

Background. Homozygous Klotho mutant mice (KL-/- mice) exhibit multiple phenotypes resembling human ageing. Increases in the ratio of urinary calcium to urinary creatinine (uCa/uCr) and in serum Ca concentration and decreases in urinary Cr excretion and serum parathyroid hormone (PTH) concentration were reported; however, precise information about renal Ca handling was not reported in these animals.

Methods. We evaluated the PTH-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in cells of isolated perfused connecting tubules (CNTs) of KL-/- mice. We also determined fractional excretion of Ca from the urine and serum samples of the same animals (n = 7), and compared them with KL+/+ mice and hemi-nephrectomized KL-+/+ mice (n = 10 in each) as controls.

Results. FECa was significantly higher in KL-/- mice than in controls (0.67 ± 0.13 vs 0.20 ± 0.04%). The PTH (10 nM)-induced increase in [Ca2+]i was diminished in KL-/- mice (58 ± 5 vs 231 ± 15 nM). Addition of 10 nM of 8-(4-chlorophenylthio)-cyclic adenosine 3',5'-monophosphate had a similar effect. The PTH-induced increase had completely disappeared by the removal of Ca from lumen and bath in both groups of animals. Removal of sodium (Na) from the solution increased [Ca2+]i to a similar extent in both groups.

Conclusion. We conclude that renal Ca excretion estimated by determining FECa was defective in the KL-/- mice. Impairment of Ca absorption from the lumen by stimulation of PTH in CNTs is one of the mechanisms of this defect. Activity of the basolateral Na/Ca exchanger was preserved in this strain. Therefore, the pathway downstream after generation of second messengers following stimulation of PTH (such as the sorting of transporters of Ca absorption) might be impaired by disruption of the Klotho gene.

Keywords: calcium absorption; connecting tubule; Klotho; PTH.
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