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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林琬琬(Wan-Wan Lin) | |
| dc.contributor.author | Chia-Che Wu | en |
| dc.contributor.author | 吳嘉哲 | zh_TW |
| dc.date.accessioned | 2021-06-15T11:30:30Z | - |
| dc.date.available | 2025-08-19 | |
| dc.date.copyright | 2020-09-02 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-19 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49476 | - |
| dc.description.abstract | 腎臟功能除了代謝廢物、排出多餘液體外，也與維持體液平衡有關。一旦腎臟血液停止供給，將會造成急性腎衰竭的發生。鈣/鈣調節蛋白依賴性絲胺酸激酶 (CASK) 是一種骨架蛋白且屬於 MAGUK 家族，在腦、骨髓及腎臟中皆有大量表現。先前的文獻提出 CASK 在腎臟的發育過程扮演關鍵性角色，但其在腎小管細胞的功能及與腎臟疾病關聯性仍然不清楚。在本篇研究中，我們探討腎小管細胞 CASK 在缺氧環境中所扮演的角色。我們發現在大鼠近曲小管上皮細胞株 (NRK-52E) 中 CASK 的蛋白表現在缺氧的條件下會上升，然而其信使核糖核酸表現量卻不受影響。此外，靜默 CASK 會抑制在缺氧條件下所誘導的血紅素氧化酶 (HO-1) 及缺氧誘導因子 (HIF-1) 蛋白表現。在 NRK-52E 細胞中，我們發現給予0.5% O2缺氧環境24小後並不會造成細胞死亡，而靜默 CASK 也不會影響細胞存活度。我們也發現在缺氧條件下靜默CASK 可以些微減緩細胞質中 ROS 的產生，但是會增加粒線體中 ROS 的含量; 至於粒線體膜電位及粒線體總量仍不受影響。值得注意的是，在正常氧濃度情況下，靜默 CASK 會降低粒線體的氧化磷酸化作用及糖解作用。NLRX1 已被報導參與調節粒線體功能，且可能與損傷疾病有關。在本研究中，我們觀察到 CASK 與 NLRX1 會共定位在細胞核中，且缺氧所誘導的NLRX1蛋白表現會受靜默 CASK所抑制。此外，我們藉由單邊或雙邊腎缺血再灌流手術，發現 CASK 無論是蛋白表現量或是基因表現量皆會在手術後受到抑制。然而在單側輸尿管阻塞誘發腎臟纖維化的疾病模式中，CASK 之基因表現量則有些上升。根據測定腎損傷標的為指標，我們發現 NLRX1 基因敲除小鼠並不會對急性腎臟疾病嚴重度產生影響，但對慢性腎臟病如腎臟纖維化的部分疾病指標則有抑制的作用。總而言之， CASK 參與腎小管細胞在正常氧環境下的代謝反應及在缺氧環境下的氧化自由基表現量的調控。對於CASK之分子作用機制、對腎臟生理及腎衰竭的病理角色仍須進一步探討。 | zh_TW |
| dc.description.abstract | The kidney plays an important function to remove the waste and excess fluid from our body and keep the right levels of electrolytes. If blood stops flowing into a kidney, can lead to acute kidney injury (AKI) and kidney failure. Calcium/calmodulin-dependent serine protein kinase (CASK), a scaffold protein, belongs to MAGUK family and is ubiquitously expressed with high expression in the brain, bone marrow and kidney. It is demonstrated that CASK plays a crucial role in kidney development, but how CASK exerts functions in renal tubular cells and involves in AKI are still unknown. Our research focused to study the role of CASK in renal tubule cells during hypoxia condition. We found in NRK-52E rat tubular epithelial cells, the protein expression of CASK is increased after hypoxic stimulation but its mRNA level is not changed. Moreover, silencing CASK can reduce hypoxia-induced HO-1 and HIF-1 protein but not gene expression. We also found that 0.5% O2 does not induce cell death in NRK-52E cells within 24 h and silencing CASK does not alter cell viability under hypoxia condition. We also demonstrated that silencing CASK slightly decreases the production of cytosolic ROS but increases the production of mitochondrial ROS under hypoxia condition without influencing the mitochondrial membrane potential nor mitochondrial mass. Of note, silencing CASK can reduce the mitochondrial respiration and glycolysis in NRK-52E cells under normoxia conditions. In addition, NOD-like receptor X1 (NLRX1) plays a role in the mitochondrial function and may involve in injury condition. In this study, we found that CASK can interact with NLRX1 in the nuclei and hypoxia-induced NLRX1 expression is inhibited by CASK silencing. Our data also revealed that the protein and/or mRNA levels of CASK are decreased in mice receiving unilateral or bilateral ischemia-reperfusion injury in kidney, while CASK mRNA is slightly increased in unilateral ureter obstruction (UUO) model. According to the injury marker, Nlrx1 knockout does not alter the progress of AKI but can reduce some disease markers of chronic kidney disease (CKD). In summary, our current findings suggest that CASK might regulate metabolism and redox status in renal tubule cells under normoxia and hypoxia conditions, respectively. The underlying molecular mechanisms are still unclear, and the pathophysiological role of CASK in AKI and CKD needs further investigation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T11:30:30Z (GMT). No. of bitstreams: 1 U0001-1208202014184800.pdf: 4653230 bytes, checksum: ea96b5cf0abc18e8f0b31d7be96b54ba (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | Contents 口試委員會審定書 i 致謝 ii Abbreviations iii Abstract v 中文摘要 vii Introduction 1 Pathogenesis and etiology of acute kidney injury 1 Novel biomarkers for AKI 3 Hypoxia in kidney injury 4 Calcium/calmodulin-dependent serine protein kinase (CASK) 6 The relationship between CASK and kidney 7 NOD-like receptor X1 (NLRX1) 8 The relationship between NLRX1 and kidney 10 Material and Methods 12 Antibodies and reagents 12 Cell culture 12 Hypoxia stimulation 13 Transfection and small interfering RNA (siRNA) 13 Infection and short hairpin RNA (shRNA) 13 Annexin V/propidium iodide (PI) staining 14 Measurement of cytosolic and mitochondrial ROS production 15 Measurement of mitochondrial oxygen consumption rate 15 Measurement of mitochondrial extracellular acidification rate 17 Immunoprecipitation 18 Immunoblotting 19 Reverse-transcription (RT) and real-time polymerase chain reaction (RT-PCR) 20 List of primer sequences 21 MTT assay 21 Animal and ethics statement 22 Ischemia/reperfusion induced acute kidney injury 22 Unilateral ureter obstruction induced chronic kidney disease 23 Renal histology and immunohistochemistry 23 Statistical analysis 24 Specific Aims 25 Results 26 CASK expression is increased after hypoxia stimulation in NRK-52E cells 26 CASK major localized in the nuclei is upregulated after hypoxia 26 Hypoxia-induced HO-1 and HIF-1 expression are inhibited by silencing CASK 27 CASK does not affect the viability of NRK-52E cells in normoxia and hypoxia 28 Hypoxia-induced ROS production is affected by silencing CASK 29 Silencing CASK does not alter mitochondrial membrane potential or mass after hypoxia stimulation 30 Silencing CASK inhibits mitochondrial respiration and glycolysis 30 Hypoxia-induced NLRX1 expression is inhibited by silencing CASK 31 CASK can interact with NLRX1 32 The role of NLRX1 in unilateral ischemia-reperfusion injury 32 The role of NLRX1 in bilateral ischemia-reperfusion injury 33 The role of NLRX1 in unilateral ureter obstruction 34 Discussion 36 The mechanism of CASK expression under hypoxia stimulation 36 How CASK regulates HIF-1HO-1 and NLRX1 protein expression 37 The role of CASK in cell death and cell growth 38 The relationship between CASK and mitochondrial function 39 The interaction between CASK and NLRX1 41 The possible functions of CASK and NLRX1 in kidney injury 41 Figures and Legends 44 Reference 63 | |
| dc.language.iso | en | |
| dc.subject | NLRX1 | zh_TW |
| dc.subject | CASK | zh_TW |
| dc.subject | 腎小管細胞 | zh_TW |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | 急性腎衰竭 | zh_TW |
| dc.subject | Renal tubular cells | en |
| dc.subject | Acute kidney injury | en |
| dc.subject | Hypoxia | en |
| dc.subject | NLRX1 | en |
| dc.subject | CASK | en |
| dc.title | 探討CASK在腎小管細胞缺氧及急性腎損傷之角色 | zh_TW |
| dc.title | The roles of CASK in hypoxic renal tubular cells and acute kidney injury | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 謝世良(Shie-Liang Hsieh),徐立中(Li-Chung Hsu),蔡丰喬(Feng-Chiao Tsai) | |
| dc.subject.keyword | CASK,腎小管細胞,缺氧,急性腎衰竭,NLRX1, | zh_TW |
| dc.subject.keyword | Renal tubular cells,Acute kidney injury,Hypoxia,CASK,NLRX1, | en |
| dc.relation.page | 73 | |
| dc.identifier.doi | 10.6342/NTU202003082 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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