Hoenderop Joost G J, van der Kemp Annemiete W C M, Urben Colleen M, Strugnell Stephen A, Bindels René J M
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, University Medical Centre Nijmegen, The Netherlands.
Kidney Int. 2004 Sep;66(3):1082-9. doi: 10.1111/j.1523-1755.2004.00858.x.
Vitamin D compounds are used clinically to control secondary hyperparathyroidism (SHPT) due to renal failure. Newer vitamin D compounds retain the suppressive action of 1,25(OH)(2)D(3) on the parathyroid glands and may have less Ca(2+)-mobilizing activity, offering potentially safer therapies.
This study investigated the effect of a single dose of compound (1,25(OH)(2)D(3), 1,24(OH)(2)D(2), or 1alpha(OH)D(2)) on renal and intestinal Ca(2+) transport proteins, including TRPV5 and TRPV6, and serum Ca(2+), in a novel SHPT model, the 25-OH-D(3)-1alpha-hydroxylase knockout mouse, which lacks endogenous 1,25(OH)(2)D(3) and is severely hypocalcemic. Animals were injected intraperitoneally with compound (100 ng/mouse).
Serum levels of 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2) peaked at four hours post-injection (pi), then declined rapidly. 1,25(OH)(2)D(2) generated from 1alpha(OH)D(2) peaked at 12 hours pi and then remained stable. Serum Ca(2+) was increased to near-normal within four hours by 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2), and within 12 hours by 1alpha(OH)D(2). 1,25(OH)(2)D(3) and 1,24(OH)(2)D(2) up-regulated duodenal TRPV5 and TRPV6 mRNA to a similar degree within four hours; mRNA levels decreased by 12 hours after 1,24(OH)(2)D(2) treatment, and by 24 hours after 1,25(OH)(2)D(3) treatment. 1,25(OH)(2)D(3) increased kidney levels of TRPV5, calbindin-D(28K), and calbindin-D(9K) mRNA within four hours; 1,24(OH)(2)D(2) did not change kidney TRPV5 levels and modestly increased calbindin D(9K) by 48 hours. 1alpha(OH)D(2) produced later-onset effects, increasing duodenal TRPV6 and calbindin-D(9K) mRNA levels by 12 hours and TRPV5 by 48 hours.
In kidney, 1alpha(OH)D(2) increased TRPV5, calbindin-D(28K), and calbindin-D(9K) mRNA levels by 12 hours. This study indicates that Ca(2+) transport proteins, including TRPV5 and TRPV6, are differentially up-regulated by vitamin D compounds.
维生素D化合物在临床上用于控制肾衰竭所致的继发性甲状旁腺功能亢进（SHPT）。新型维生素D化合物保留了1,25(OH)₂D₃对甲状旁腺的抑制作用，且可能具有较弱的钙动员活性，有望提供更安全的治疗方法。
本研究在一种新型SHPT模型——25-OH-D₃-1α-羟化酶基因敲除小鼠中，研究了单剂量化合物（1,25(OH)₂D₃、1,24(OH)₂D₂或1α(OH)D₂）对肾脏和肠道钙转运蛋白（包括TRPV5和TRPV6）以及血清钙的影响。该基因敲除小鼠缺乏内源性1,25(OH)₂D₃且严重低钙血症。动物腹腔注射化合物（100 ng/只小鼠）。
1,25(OH)₂D₃和1,24(OH)₂D₂的血清水平在注射后4小时达到峰值，然后迅速下降。由1α(OH)D₂生成的1,25(OH)₂D₂在注射后12小时达到峰值，然后保持稳定。1,25(OH)₂D₃和1,24(OH)₂D₂在4小时内使血清钙升高至接近正常水平，1α(OH)D₂在12小时内使血清钙升高至接近正常水平。1,25(OH)₂D₃和1,24(OH)₂D₂在4小时内使十二指肠TRPV5和TRPV6 mRNA上调至相似程度；1,24(OH)₂D₂处理后12小时mRNA水平下降，1,25(OH)₂D₃处理后24小时mRNA水平下降。1,25(OH)₂D₃在4小时内使肾脏TRPV5、钙结合蛋白-D₂₈K和钙结合蛋白-D₉K mRNA水平升高；1,24(OH)₂D₂在48小时内未改变肾脏TRPV5水平，但适度升高了钙结合蛋白-D₉K水平。1α(OH)D₂产生延迟效应，在12小时时使十二指肠TRPV6和钙结合蛋白-D₉K mRNA水平升高，在48小时时使TRPV5水平升高。
在肾脏中，1α(OH)D₂在12小时时使TRPV5、钙结合蛋白-D₂₈K和钙结合蛋白-D₉K mRNA水平升高。本研究表明，包括TRPV5和TRPV6在内的钙转运蛋白受维生素D化合物的上调作用存在差异。
