Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice
Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice
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DOI：
10.1681/asn.2006060676
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发表时间：
2006-11-01
影响因子：
13.6
通讯作者：
Hoenderop, Joost G.
中科院分区：
文献类型：
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作者：
Gkika, Dimitra;Hsu, Yu-Juei;Hoenderop, Joost G.
上皮性钙通道TRPV5在远曲小管活性钙重吸收过程中促进心尖钙内流。在这个过程中，由于钙结合蛋白-D-28K能迅速缓冲钙离子的内流，细胞内的钙离子保持在较低的无毒浓度。随后，与Calbindin-D-28K结合的Ca~(2+)被穿梭到基侧的Ca~(2+)挤出系统。为了探讨TRPV5和Calbindin-D-28K在体内维持钙平衡中的作用，对TRPV5和calbindin-D-28K(TRPV5(-/-)、calbindin-D-28K(-/-)和TRPV5(-/-)/caIbindin-D-28K(-/-))单基因敲除和双基因敲除小鼠进行了鉴定。分别饲喂0.02和2%(wt/wt)两种钙离子饲料，研究饲料中钙离子含量对钙平衡的影响。尿液分析显示，与野生型小鼠相比，TRPV5(-/-)/calbindin-D-28K(-/-)小鼠在两种饮食中均表现出高钙尿。TRPV5(-/-)/calbindin-D(28K)(-/-)小鼠的钙排泄与TRPV5(-/-)小鼠无显著差异，而calbindin-D-28K(-/-)小鼠未见高钙。TRPV5(-/-)/calbindinD(28K)(-/-)小鼠与TRPV5(-/-)小鼠之间的相似性进一步得到了肾脏Calbindin-D-9K表达的增加和十二指肠Calbindin-D-9K和TRPV6表达上调导致的肠道钙高吸收的进一步支持。血清甲状旁腺激素和1，25-二羟基维生素D-3水平升高伴随着钙离子转运体表达的增强。Calbindin-D28K(-/-)小鼠的肠道钙吸收、钙结合蛋白-Dik和TRPV6的表达以及血清参数与野生型小鼠无明显差异。这些结果表明，与Calbindin-D-28K不同，TRPV5是主动重吸收钙离子的限速步骤，它可能被Calbindin-D-9K补偿。
The epithelial Ca2+ channel TRPV5 facilitates apical Ca2+ entry during active Ca" reabsorption in the distal convoluted tubule. In this process, cytosolic Ca" remains at low nontoxic concentrations because the Ca" influx is buffered rapidly by calbindin-D-28K. Subsequently, Ca2+ that is bound to calbindin-D-28K is shuttled toward the basolateral Ca2+ extrusion systems. For addressing the in vivo role of TRPV5 and calbindin-D-28K in the maintenance of the Ca2+ balance, single- and doubleknockout mice of TRPV5 and calbindin-D-28K (TRPV5(-/-), calbindin-D-28K(-/-), and TRPV5(-/-)/caIbindin-D-28K(-/-)) were characterized. These mice strains were fed two Ca2+ diets (0.02 and 2% wt/wt) to investigate the influence of dietary Ca2+ content on the Ca2+ balance. Urine analysis indicated that TRPV5(-/-)/calbindin-D-28K(-/-) mice exhibit on both diets hypercalciuria compared with wild-type mice. Ca2+ excretion in TRPV5(-/-)/calbindin-D(28K)(-/-)mice was not significantly different from TRPV5(-/-) mice, whereas calbindin-D-28K(-/-) mice did not show hypercalciura. The similarity between TRPV5(-/-)/calbindinD(28K)(-/-) and TRPV5(-/-) mice was supported further by an equivalent increase in renal calbindin-D-9K expression and in intestinal Ca2+ hyperabsorption as a result of upregulation of calbindin-D-9K and TRPV6 expression in the duodenum. Elevated serum parathyroid hormone and 1,25-dihydroxyvitamin D-3 levels accompanied the enhanced expression of the Ca2+ transporters. Intestinal Ca" absorption and expression of calbindin-DIK and TRPV6, as well as serum parameters of the calbindin-D28K(-/-) mice, did not differ from those of wild-type mice. These results underline the gatekeeper function of TRPV5 being the rate-limiting step in active Ca2+ reabsorption, unlike calbindin-D-28K, which possibly is compensated by calbindin-D-9K.