Favus M J
Department of Medicine, University of Chicago Pritzker School of Medicine, IL 60637.
J Am Soc Nephrol. 1994 Nov;5(5 Suppl 1):S54-8. doi: 10.1681/ASN.V55s54.
Human idiopathic hypercalciuria (IH) is a common cause of hypercalciuria that contributes to calcium oxalate nephrolithiasis. The disorder is characterized by normocalcemia, increased intestinal Ca absorption, and normal or elevated circulating 1,25(OH)2D3. Intestinal Ca hyperabsorption, which is a source of excess urine Ca excretion, may result from either a primary increase in renal 1,25(OH)2D3 production; a primary, vitamin D-independent defect in enterocyte regulation of Ca transport; or a secondary increase in 1,25(OH)2D3 production in response to a defect in renal tubular Ca reabsorption. Breeding male and female Sprague Dawley rats with spontaneous hypercalciuria has resulted in offspring with hypercalciuria, increased intestinal Ca absorption, and normal serum 1,25(OH)2D3. In male IH rats, vitamin D receptor (VDR) content measured by saturation binding and western blotting revealed a twofold increase in VDR number in the duodenum, kidney cortex, and splenic monocytes. The molecular basis for the increase in VDR appears not to be due to increased VDR gene expression, but may result from increased efficiency of translation of the VDR message or prolongation of the half-life of VDR. Comparable migration of normal and IH intestinal VDR on western blots and of intestinal VDR mRNA on northern blots suggests that the abundant VDR in IH rat intestine is not a mutation of the wild-type VDR. These observations strongly suggest that, in IH rats, normal serum 1,25(OH)2D3 and increased VDR results in increased VDR-1,25(OH)2D3 complexes and enhanced biologic actions of 1,25(OH)2D3, including increased intestinal Ca transport. IH in rats may be the first genetic disorder due to a pathologic increase in the VDR.
人类特发性高钙尿症（IH）是导致高钙尿症的常见原因，可引发草酸钙肾结石。该病症的特征为血钙正常、肠道钙吸收增加以及循环中的1,25(OH)2D3正常或升高。肠道钙吸收增加是尿钙排泄过多的一个来源，其可能源于以下原因：一是肾脏1,25(OH)2D3生成的原发性增加；二是肠细胞钙转运调节中存在原发性、不依赖维生素D的缺陷；或者是由于肾小管钙重吸收缺陷导致1,25(OH)2D3生成的继发性增加。对患有自发性高钙尿症的雄性和雌性斯普拉格-道利大鼠进行繁殖，其后代出现了高钙尿症、肠道钙吸收增加以及血清1,25(OH)2D3正常的情况。在雄性IH大鼠中，通过饱和结合和蛋白质印迹法测量维生素D受体（VDR）含量，结果显示十二指肠、肾皮质和脾单核细胞中的VDR数量增加了两倍。VDR增加的分子基础似乎并非由于VDR基因表达增加，而是可能源于VDR信息翻译效率提高或VDR半衰期延长。正常和IH肠道VDR在蛋白质印迹上的迁移以及肠道VDR mRNA在Northern印迹上的迁移情况具有可比性，这表明IH大鼠肠道中丰富的VDR并非野生型VDR的突变。这些观察结果有力地表明，在IH大鼠中，正常的血清1,25(OH)2D3和增加的VDR会导致VDR - 1,25(OH)2D3复合物增加以及1,25(OH)2D3的生物学作用增强，包括肠道钙转运增加。大鼠的IH可能是由于VDR病理性增加导致的首例遗传性疾病。
