Insights into Driving Forces and Paracellular Permeability from Claudin-16 Knockdown Mouse
Insights into Driving Forces and Paracellular Permeability from Claudin-16 Knockdown Mouse
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DOI：
10.1111/j.1749-6632.2009.04041.x
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
Bleich, Markus
中科院分区：
文献类型：
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作者：
Shan, Qixian;Himmerkus, Nina;Bleich, Markus
紧密连接（TJ）的性质是由相邻细胞的膜蛋白复合物决定的，这些膜蛋白复合物形成细胞旁底物转运的屏障和选择性途径。我们以前的工作支持这样的观点，即粗升支（TAL）中的细胞旁通透性变化可能是家族性低镁血症伴高钙尿症和肾钙质沉着症（FHHNC）的机制的基础，FHHNC是一种与claudin-16（CLDN 16）和claudin-19（CLDN 19）突变相关的罕见常染色体隐性遗传病。CLDN 16敲低（KD）小鼠通过转基因RNA干扰缺乏CLDN 16表达。我们观察到，在这个动物模型中的Mg 2+和Ca 2+的转运缺陷是由细胞旁阳离子选择性的损失引起的。与野生型（WT）相比，KD小鼠中Na+与Cl-的渗透率比降低了2倍，而细胞旁电导没有变化。这导致跨上皮电压的崩溃，跨上皮电压是TAL中Mg 2+和Ca 2+吸收的驱动力。由于CLDN 16 KD小鼠显示血压降低和醛固酮血浆浓度增加，我们假设细胞旁选择性的降低可以允许Na+和Cl-回流到TAL的管腔中，从而增强远端NaCl负荷并以潜在的NaCl损失挑战生物体。
Tight junction (TJ) properties are determined by membrane protein complexes of neighboring cells that form both a barrier and a selective pathway for paracellular substrate transport. Our previous work supports the view that paracellular permeability changes in the thick ascending limb (TAL) may underlie the mechanism for familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a rare autosomal recessive disease linked to mutations in claudin-16 (CLDN16) and claudin-19 (CLDN19). CLDN16 knockdown (KD) mice are lacking CLDN16 expression by transgenic RNA interference. We observed that the transport defect for Mg2+ and Ca2+ in this animal model is caused by a loss of paracellular cation selectivity. The permeability ratio for Na+ over Cl- in KD mice was lower by a factor of two without a change in paracellular conductance, compared to wild type (WT). This resulted in a collapse of the transepithelial voltage, which is the driving force for Mg2+ and Ca2+ absorption in TAL. Since CLDN16 KD mice revealed lower blood pressure and an increased aldosterone plasma concentration, we hypothesize that the reduction in paracellular selectivity could allow backflow of Na+ and Cl- into the lumen of the TAL, thus enhancing the distal NaCl load and challenging the organism with a latent NaCl loss.