- 學位論文
過氧化體增殖劑活化受器α 透過鈉氫離子交換蛋白訊 號傳遞路徑抑制Gentamicin 所造成之腎小管細胞凋亡
Peroxisome proliferator-activated receptor alpha inhibits the gentamicin-induced apoptosis in renal tubular cells through Na+/H+ exchanger-1 signaling pathway
摘要
Gentamicin 能抑制細菌的蛋白質合成與複製，並且具有較低的抗藥性因而 廣泛地被使用於治療格蘭氏陰性菌的感染上。Gentamicin 經由肌肉或靜脈注射 進入人體後主要是由腎臟代謝排出體外，但仍有少量的gentamicin 會被在吸收 並且累積於腎小管內，目前已證實會使腎小管細胞凋亡、壞死而引起急性腎衰 竭。而急性腎衰竭對於腎臟的傷害難以恢復，且無明確的藥物治療方法。過氧 化體增殖劑活化受器PPARα，具有ligand-activated nuclear receptor 的特性，近期發現能降低腎小管細胞凋亡現象，但其詳細的作用機制尚未被探討。在本文中透過檢測pH 值變化與細胞大小變化，發現PPARα 會增加NHE1 活性。 NHE1 亦會與細胞骨架相關訊息傳遞蛋白ERM 及訊息傳遞分子PIP2 交互作 用，避免gentamicin 造成的細胞凋亡，而ERM siRNA 會降低免於細胞凋亡的 效果。此外，NHE1 增加PI3K 表現，進而增加Akt 磷酸化，活化下游抗細胞凋 亡的訊息傳遞路徑，而PI3K 抑制劑減少Akt 磷酸化，降低保護細胞免於凋亡 的效果。透過探討NHE1 作用機制，更能了解PPARα 對細胞的保護作用，並且 未來能以PPARα 作為治療的標的。
並列摘要
Gentamicin is a widely used antibiotic drug, but also causes severe nephrotoxicity and acute kidney injury (AKI) by inducing renal tubular cell apoptosis. Peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated nuclear receptor, was reported to prevent renal tubular cells from apoptosis but the detailed mechanism is unknown. In this study, we found that PPARα increased the sodium hydrogen exchanger-1(NHE1) expression. We also found the NHE1 activity increased in PPARα-overexpressed cells as revealed by pH recovery assay and cell volume increase analysis. NHE1 interacted with Ezrin/Radixin/Moesin (ERM) and phosphatidylinositol 4, 5-bisphosphate [PI (4, 5) P2] to protect cells from gentamicininduced apoptosis. ERM siRNA reduced the antiapoptotic effect in PPARα- overexpressed cells. NHE1 also induced PI3K expression to block gentamicininduced apoptosis in PPARα-overexpressed cells, which was inhibited by NHE1 inhibitor 5-(N-ethyl-N-isopropyl)-Amiloride (EIPA). The PI3K increase induced phosphorylation of Akt in PPARα-overexpressed cells, and the PI3K inhibitor wortmannin reduced the phosphorylated Akt. NHE1 plays an important role in the PPARα renal protective effect and might be a potential therapeutic for gentamicininduced kidney injury.
參考文獻
延伸閱讀
- Chen, B. L. (2015). CHOP蛋白、氧化壓力及發炎反應在腎臟缺血再灌流引起細胞凋亡上之角色探討 [doctoral dissertation, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU.2015.11234
- Cheng, C. Y. (2008). Celecoxib抑制腎小管細胞經壓力所導致之轉化生長因子b表現及細胞外間質之生成 [master's thesis, Taipei Medical University]. Airiti Library. https://doi.org/10.6831/TMU.2008.00101
- Hung, C. T. (2020). 基因剃除血栓烷A2合成酶和血栓烷前列腺素接受器訊息對腎缺血再灌流引起之氧化傷害效益 [doctoral dissertation, National Taiwan Normal University]. Airiti Library. https://doi.org/10.6345/NTNU202001423
- Grau, R., Muñoz, M. D. D., Llaguno, C. C., Fresno, M., & Iñiguez, M. A. (2008). Role of Peroxisome Proliferator-Activated Receptor Alpha in the Control of Cyclooxygenase 2 and Vascular Endothelial Growth Factor: Involvement in Tumor Growth. PPAR Research, 2008(), 507-516-046. https://doi.org/10.1155/2008/352437
- González, M. D. C., Corton, J. C., Acero, N., Mingarro, D. M., Quirós, Y., Millán, J. J. Á., Herrera, E., & Bocos, C. (2012). Peroxisome Proliferator-Activated Receptorα Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells. PPAR Research, 2012(), 363-371. https://doi.org/10.1155/2012/483536