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N-Methyl-D-Aspartate Receptor Subunit NR3a Expression and Function in Principal Cells of the Collecting Duct.

机译：N-甲基-D-天冬氨酸受体亚基NR3a在收集导管的主要细胞中的表达和功能。

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摘要

N-Methyl-D-Aspartate Receptors (NMDARs) are Ca2+-permeable, ligand gated, non-selective cation channels that function as neuronal synaptic receptors but which are also expressed in multiple peripheral tissues. Here we show that NMDAR subunits NR3a and NR3b are highly expressed in the neonatal mouse kidney and that there is continued expression of NR3a in the renal medulla and papilla of the adult mouse. NR3a was also expressed in an inner medullary collecting duct cell line (mIMCD-3) where it was found that hypoxia and hypertonicity up-regulated NR3a expression. Using shRNA-based knockdown, a stable IMCD cell line was established that had ∼80% decrease in NR3a. Knockdown cells exhibited an increased basal intracellular free calcium concentration, reduced cell proliferation, and increased cell death. In addition NR3a knockdown cells exhibited reduced water transport in response to the addition of vasopressin, suggesting an alteration in aquaporin-2 (AQP2) expression/function. Consistent with this notion, we demonstrate decreased surface expression of glycosylated AQP2 in IMCD cells transfected with NR3a shRNA. To determine if this also occurred in vivo, we compared AQP2 levels in wild type versus in NR3a -/- mice. Total AQP2 protein levels in the outer and inner medulla were significantly reduced in knockout mice compared to control mice. Finally, NR3a-/- mice showed a significant delay in their ability to increase urine osmolality during water restriction. Thus, NR3a may play a reno-protective role in collecting duct cells. Under conditions that are associated with high vasopressin levels, NR3a, by maintaining low intracellular calcium levels, protects the function of the principal cells to reabsorb water and thereby increase medullary osmolality, which is essential for urinary concentration and dilution.
机译：N-甲基-D-天门冬氨酸受体（NMDARs）是可渗透Ca2 +的，配体门控的非选择性阳离子通道，可充当神经元突触受体，但也可在多个外周组织中表达。在这里，我们显示NMDAR亚基NR3a和NR3b在新生小鼠肾脏中高度表达，并且NR3a在成年小鼠的肾脏髓质和乳头中持续表达。 NR3a在内侧髓样收集管细胞系（mIMCD-3）中也表达，发现缺氧和高渗会上调NR3a的表达。使用基于shRNA的敲除，建立了稳定的IMCD细胞系，其NR3a减少了约80％。击倒细胞表现出增加的基础细胞内游离钙浓度，减少的细胞增殖和增加的细胞死亡。另外，响应于加压素的添加，NR3a敲低的细胞表现出减少的水运输，表明水通道蛋白2（AQP2）表达/功能的改变。与此概念一致，我们证明了在NR3a shRNA转染的IMCD细胞中糖基化AQP2的表面表达降低。为了确定这是否还发生在体内，我们比较了野生型和NR3a-/-小鼠的AQP2水平。与对照小鼠相比，基因敲除小鼠的外部和内部髓质中的总AQP2蛋白水平显着降低。最后，NR3a-/-小鼠在禁水期间增加尿渗透压的能力显着延迟。因此，NR3a可能在收集导管细胞中起着肾脏保护的作用。在与高血管加压素水平相关的条件下，NR3a通过维持低细胞内钙水平来保护主要细胞的功能，使其重吸收水，从而增加髓质渗透压，这对尿液的浓缩和稀释至关重要。

著录项

  • 作者

    Sproul, Adrian David.;

  • 作者单位

    Medical University of South Carolina.;

  • 授予单位 Medical University of South Carolina.;
  • 学科 Biology Cell.;Biology Animal Physiology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 118 p.
  • 总页数 118
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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