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The Role of TonEBP in Regulation of AAD Expression and Dopamine Production in Renal Proximal Tubule Cells upon Hypertonic Challenge
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|摘要:||先前研究已知高張環境會促使TonEBP(TonE binding protein)活化進而增強下游基因的表現。腎臟近曲小管細胞藉由過度表現AAD (aromatic L-amino acid decarboxylase)來合成多巴胺達到抑制腎臟對鹽類的吸收。本篇研究利用人類近曲小管細胞，HK-2 (Human renal proximal tubule cell)來探討TonEBP對於AAD表現的調控機制。利用共軛焦螢光顯微鏡觀察到2小時的高張刺激下TonEBP會大量的堆積在細胞核中，且已知的下游調控基因如SMIT與TauT mRNA亦會大量表現。此外，隨著TonEBP的活化會造成AAD蛋白質的表現量增加。EMSA與luciferase reporter assay的實驗結果顯示TonEBP參與在AAD的轉錄作用中。利用p38抑制劑SB203580或專一性shRNA干擾TonEBP的活化均會減少AAD的蛋白質表現。除此之外，利用Myc-TonEBP重新表現在TonEBP shRNA的細胞中會再度提高AAD的表現。高張刺激下AAD的大量表現確實會增加多巴胺的合成進而抑制NKA的活性使得細胞的存活率增加。由上述結果推測，在腎臟近曲小管面臨高張環境下TonEBP可能扮演著抑制鹽類吸收的主要調控者，同時對細胞產生保護的角色。|
Hypertonic environment induces TonE binding protein (TonEBP) activation and enhances expression of downstream genes. Renal proximal tubule cells overexpress aromatic L-amino acid decarboxylase (AAD) to produce dopamine, which inhibits salt absorption in the hypertonic environment. We examined the effect of TonEBP on AAD expression in human proximal tubule epithelial cells, HK-2 cell line. Confocal microscopy showed that after 2 h of exposure to the hypertonic medium, TonEBP accumulation in nuclei increased as compared to the isotonic control group. The activated TonEBP enhanced the mRNA expression of the representative downstream genes (i.e., SMIT and TauT). Meanwhile, AAD protein abundance also increased with TonEBP activation. EMSA and luciferase reporter assay showed that TonEBP was involved in transcriptional regulation of AAD upon hypertonic stress. Inactivation of TonEBP by the p38 inhibitor SB203580, or TonEBP silencing with specific shRNA significantly reduced AAD expression, which was rescued by re-expressing Myc-tagged TonEBP. Up-regulation of AAD increased dopamine synthesis, and dopamine inhibited NKA activity in hypertonic condition. Furthermore, the effects of dopamine on inhibition of NKA activity would increase cell viability upon hypertonic stress. These results suggested that TonEBP played a cytoprotective role in the epithelial cells of renal proximal tubule upon hypertonic stress by enhancing AAD expression, which could promote dopamine secretion to rescue cell viability. The elucidation of a new mechanism described in this study combined with previous findings provides more insights into this issue.
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