Role of PON3 in regulating renal Na+ and K+ homeostasis

摘要 哺乳动物对氧磷酶(PON)家族由三个高度保守的成员组成(PON1， PON2和PON3)具有独特的抗氧化和抗动脉粥样硬化特性。PON1和2 与血压(BP)调节有关。而PON3在调节血压中的作用 尚未被研究，它表达在对醛固酮敏感的远端肾单位，其中 Na+吸收和K+分泌发生微调。PON共享关键的结构和功能 线虫的内质网驻留伴侣MEC-6的特征。MEC-6是 机械敏感型退变的正确折叠、组装和表面表达所需 触觉感受器神经元中的通道。哺乳动物之间的伴侣功能是保守的 Pons和线虫MEC-6。我们之前已经证明PON2和PON3都调节 上皮性钠离子通道(ENaC)的功能表达 离子通道家族。ENAC介导远端肾单位Na+重吸收的限速步骤 并且在容量和血压控制方面起着关键作用。而构成K+的分泌是由 肾脏外髓K+通道、ENaC依赖和血流诱导的K+分泌 是由大电导K+(BK)通道介导的。在初步研究中，我们发现， Pon3KO小鼠具有更高的ENaC活性和增强的阿米洛利敏感性钠尿， 提示在没有PON3的情况下，ENaC的功能表达上调。此外，我们 已经确定BK通道是PON3的一个新靶点。在HEK293细胞中表达时，PON3 与BKα亚基相互作用，降低其表面表达和通道活性。我们的建议 研究将确定PON3作为伴侣调节的机制 ENAC和BK的表达。我们将确定删除肾脏Na+中PON3的后果 K+处理和血压控制。顺利完成我们建议的研究将加强 我们对脑桥作为伴侣的作用机制及其作用的理解 在肾功能和血压控制中的生理作用。

ABSTRACT The mammalian paraoxonase (PON) family consists of three highly conserved members (PON1, PON2 and PON3) with unique anti-oxidative and anti-atherosclerotic properties. PON1 and 2 have been implicated in blood pressure (BP) regulation. While the role of PON3 in regulating BP has not been investigated, it is expressed in the aldosterone-sensitive distal nephron where the fine tuning of Na+ absorption and K+ secretion occurs. PONs share key structural and functional features with MEC-6, an endoplasmic reticulum-resident chaperone of C. elegans. MEC-6 is required for proper folding, assembly, and surface expression of the mechanosensitive degenerin channel in touch receptor neurons. The chaperon function is conserved between mammalian PONs and C. elegans MEC-6. We have previously shown that both PON2 and PON3 regulate functional expression of the epithelial Na+ channel (ENaC), a member of the ENaC/degenerin family of ion channels. ENaC mediates the rate-limiting step of Na+ reabsorption in distal nephron and has a key role in volume and BP control. While the constitutive K+ secretion is conducted by the renal outer medullary K+ (ROMK) channels, ENaC-dependent and flow-induced K+ secretion is mediated by the large conductance K+ (BK) channels. In the preliminary studies, we found that Pon3 KO mice have higher ENaC activity and enhanced amiloride-sensitive natriuresis, suggesting ENaC functional expression is upregulated in the absence of PON3. In addition, we have identified BK channel as a novel target of PON3. When expressed in HEK293 cells, PON3 interacted with BK α subunit to reduce its surface expression and channel activity. Our proposed studies will define mechanisms by which PON3 functions as a chaperone in the regulation of ENaC and BK expression. We will determine the consequences of deleting PON3 in renal Na+ and K+ handling and BP control in mice. Successful completion our proposed studies will enhance our understanding of the mechanisms by which PONs function as chaperones and their physiological roles in kidney function and BP control.