van Abel Monique, Huybers Sylvie, Hoenderop Joost G J, van der Kemp Annemiete W C M, van Leeuwen Johannes P T M, Bindels René J M
Department of Physiology, Nijmegen Centre for Molecualr Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Am J Physiol Renal Physiol. 2006 Dec;291(6):F1177-83. doi: 10.1152/ajprenal.00038.2006. Epub 2006 May 16.
Aging is associated with alterations in Ca2+ homeostasis, which predisposes elder people to hyperparathyroidism and osteoporosis. Intestinal Ca2+ absorption decreases with aging and, in particular, active transport of Ca2+ by the duodenum. In addition, there are age-related changes in renal Ca2+ handling. To examine age-related changes in expression of the renal and intestinal epithelial Ca2+ channels, control (TRPV5+/+) and TRPV5 knockout (TRPV5-/-) mice aged 10, 30, and 52 wk were studied. Aging of TRPV5(+/+) mice resulted in a tendency toward increased renal Ca2+ excretion and significantly decreased intestinal Ca2+ absorption, which was accompanied by reduced expression of TRPV5 and TRPV6, respectively, despite increased serum 1,25(OH)2D3 levels. Similarly, in TRPV5-/- mice the existing renal Ca2+ loss was more pronounced in elder animals, whereas the compensatory intestinal Ca2+ absorption and TRPV6 expression declined with aging. In both mice strains, aging resulted in a resistance to 1,25(OH)2D3 and diminished renal vitamin D receptor mRNA levels, whereas serum Ca2+ levels remained constant. Furthermore, 52-wk-old TRPV5-/- mice showed severe hyperparathyroidism, whereas PTH levels in elder TRPV5+/+ mice remained normal. In 52-wk-old TRPV5-/- mice, serum osteocalcin levels were increased in accordance with the elevated PTH levels, suggesting an increased bone turnover in these mice. In conclusion, downregulation of TRPV5 and TRPV6 is likely involved in the impaired Ca2+ (re)absorption during aging. Moreover, TRPV5-/- mice likely develop age-related hyperparathyroidism and osteoporotic characteristics before TRPV5+/+ mice, demonstrating the importance of the epithelial Ca2+ channels in Ca2+ homeostasis.
衰老与钙稳态的改变有关，这使老年人易患甲状旁腺功能亢进和骨质疏松症。随着年龄增长，肠道钙吸收减少，尤其是十二指肠对钙的主动转运。此外，肾脏对钙的处理也存在与年龄相关的变化。为了研究肾脏和肠道上皮钙通道表达的年龄相关变化，我们对10周、30周和52周龄的对照（TRPV5+/+）和TRPV5基因敲除（TRPV5-/-）小鼠进行了研究。TRPV5(+/+)小鼠的衰老导致肾脏钙排泄有增加的趋势，肠道钙吸收显著减少，尽管血清1,25(OH)2D3水平升高，但分别伴随着TRPV5和TRPV6表达的降低。同样，在TRPV5-/-小鼠中，现有的肾脏钙流失在老年动物中更为明显，而代偿性肠道钙吸收和TRPV6表达则随着年龄增长而下降。在两种小鼠品系中，衰老导致对1,25(OH)2D3的抵抗以及肾脏维生素D受体mRNA水平降低，而血清钙水平保持恒定。此外，52周龄的TRPV5-/-小鼠表现出严重的甲状旁腺功能亢进，而老年TRPV5+/+小鼠的甲状旁腺激素水平保持正常。在52周龄的TRPV5-/-小鼠中，血清骨钙素水平随着甲状旁腺激素水平的升高而增加，表明这些小鼠的骨转换增加。总之，TRPV5和TRPV6的下调可能与衰老过程中钙（再）吸收受损有关。此外，TRPV5-/-小鼠可能比TRPV5+/+小鼠更早出现与年龄相关的甲状旁腺功能亢进和骨质疏松特征，证明了上皮钙通道在钙稳态中的重要性。
