Maritzen T, Rickheit G, Schmitt A, Jentsch T J
Zentrum für Molekulare Neurobiologie Hamburg, ZMNH, Universität Hamburg, Hamburg, Germany.
Kidney Int. 2006 Jul;70(1):79-87. doi: 10.1038/sj.ki.5000445. Epub 2006 May 3.
Mutations in ClC-5 cause Dent's disease, a disorder associated with low molecular weight proteinuria, hyperphosphaturia, and kidney stones. ClC-5 is a Cl(-)/H(+)-exchanger predominantly expressed in the kidney, where it facilitates the acidification of proximal tubular endosomes. The reduction in proximal tubular endocytosis resulting from a lack of ClC-5 raises the luminal concentration of filtered proteins and peptides like parathyroid hormone (PTH). The increase in PTH may explain the hyperphosphaturia observed in Dent's disease. Expression profiling, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and hormone measurements were used to investigate whether the disruption of ClC-5 affects other signalling pathways. Although the upregulation of 25(OH)(2)-vitamin D(3) 1alpha-hydroxylase and downregulation of vitamin D(3) 24-hydroxylase suggested an increased formation of 1,25(OH)(2)-vitamin D(3), the concentration of this active metabolite was reduced in the serum of ClC-5 knockout (KO) mice. However, target genes of 1,25(OH)(2)-vitamin D(3) were upregulated in KO kidneys. Expression analysis of intestine and bone revealed that the upregulation of 1,25(OH)(2)-vitamin D(3) target genes was kidney intrinsic and not systemic. In spite of reduced serum levels of 1,25(OH)(2)-vitamin D(3) in ClC-5 KO mice, 1,25(OH)(2)-vitamin D(3) is increased in later nephron segments as a consequence of impaired proximal tubular endocytosis. This leads to a kidney-specific stimulation of 1,25(OH)(2)-vitamin D(3) target genes that may contribute to the pathogenesis of Dent's disease. The activation of genes in distal nephron segments by hormones that are normally endocytosed in the proximal tubule may extend to other pathways like those activated by retinoic acid.
ClC-5基因的突变会导致丹特氏病，这是一种与低分子量蛋白尿、高磷尿症和肾结石相关的疾病。ClC-5是一种主要在肾脏中表达的Cl(-)/H(+)交换体，它促进近端肾小管内体的酸化。由于缺乏ClC-5导致近端肾小管内吞作用减少，从而提高了滤过蛋白和肽（如甲状旁腺激素（PTH））的管腔浓度。PTH的增加可能解释了丹特氏病中观察到的高磷尿症。采用表达谱分析、定量逆转录聚合酶链反应（qRT-PCR）和激素测量来研究ClC-5的破坏是否会影响其他信号通路。虽然25(OH)(2)-维生素D(3) 1α-羟化酶的上调和维生素D(3) 24-羟化酶的下调表明1,25(OH)(2)-维生素D(3)的生成增加，但在ClC-5基因敲除（KO）小鼠的血清中，这种活性代谢物的浓度却降低了。然而，1,25(OH)(2)-维生素D(3)的靶基因在KO小鼠的肾脏中上调。肠道和骨骼的表达分析表明，1,25(OH)(2)-维生素D(3)靶基因的上调是肾脏固有的，而非全身性的。尽管ClC-5 KO小鼠血清中1,25(OH)(2)-维生素D(3)水平降低，但由于近端肾小管内吞作用受损，1,25(OH)(2)-维生素D(3)在肾单位后期节段中增加。这导致了肾脏特异性地刺激1,25(OH)(2)-维生素D(3)靶基因，这可能有助于丹特氏病的发病机制。通常在近端小管内被内吞的激素对远端肾单位节段基因的激活可能会扩展到其他途径，如视黄酸激活的途径。
