臺灣博碩士論文加值系統

急性腎衰竭為致命性疾病，歸因於許多因素包含敗血症；而敗血性急性腎衰竭極具高致死率且尚無有效的治療方法。研究發現，過量表現的促發炎細胞激素腫瘤壞死因 (TNF) 及細胞凋亡現象在敗血性急性腎衰竭的致病機轉中扮演重要的角色。肝醣合成酶激酶-3 (GSK-3) 被證實具有促發炎及促細胞凋亡的生物功能，我們假設抑制GSK-3的作用將可改善敗血性急性腎衰竭。實驗發現GSK-3抑制劑包括鋰鹽、6-bromo- indirubin-3’-oxime (BIO) 以及4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5- dione (TDZD) 有效地降低內毒素脂多醣體 (LPS) 誘發小鼠的致死率。組織及血清分析的結果顯示GSK-3抑制劑減緩腎臟中腎小管擴張、空泡化和脫落的病變，並可降低血清中尿素氮的表現量。利用酵素免疫吸附分析法進一步發現在LPS處置的小鼠血清中及小鼠皮質集尿管上皮細胞株 (M1) 培養液中，抑制GSK-3可降低細胞激素TNF以及化學趨化激素RANTES並提高抗發炎細胞激素-介白素10 (IL-10) 的表現量。我們進而發現抑制GSK-3可以減少LPS誘發轉錄因子NF-kappaB從細胞質轉移至細胞核的表現。另外，抑制GSK-3可以減少TNF於大鼠近曲小管上皮細胞株 (NRK52E) 促使誘發型一氧化氮生成酶的表現。因此，我們推測LPS和TNF活化發炎反應的過程中係透過GSK-3依賴性的調控機制。除了抗發炎作用，GSK-3抑制劑可以降低體內LPS誘發小鼠腎臟組織中的細胞凋亡現象。我們進而證明體外模式給予TNF可造成大鼠近曲小管上皮細胞株的死亡，然而體外模式給予LPS並無此效應。然而，GSK-3抑制劑只能輕微減緩TNF造成細胞死亡的現象。綜合而論，我們的實驗結果顯示抑制GSK-3可以減緩LPS誘發TNF的表現以提供抗發炎及抗細胞凋亡的保護作用進而改善敗血性急性腎衰竭的發生。

Acute renal failure (ARF) is a fatal disease and attributed to many reasons including sepsis; septic ARF is characterized by high mortality rate; nevertheless, an efficient therapy for improving septic ARF remains unavailable. Excessive tumor necrosis factor-alpha (TNF-alpha) and apoptosis play pathogenic roles in endotoxemia-induced ARF. A lot of studies have shown that glycogen synthase kinase (GSK-3) promotes inflammation such as TNF-alpharelease and enhances apoptosis. Since GSK-3 plays an emergency role in inflammation and apoptosis, we hypothesize that inhibiting GSK-3 may improve septic ARF. By histology and serology analyses, GSK-3 inhibitors inhibited renal tubular dilatation, vacuolization and sloughing and caused down-regulation in blood urea nitrogen in lipopolysaccharide (LPS)-treated C3H/HeN mice. ELISA analysis further showed that inhibiting GSK-3 decreased systemic TNF-alpha and regulated upon activation normal T-cell expressed and secreted but increased anti-inflammatory interleukin-10 (IL-10) in LPS-treated mice and murine kidney cortical collecting duct epithelial M1 cells. Further in vitro studies demonstrated that LPS-induced
NF-kappaB nuclear translocation was blocked by GSK-3 inhibition. Additionally, inhibiting GSK-3 efficiently decreased TNF-alpha-induced inducible nitric oxide synthase expression in rat kidney proximal tubular epithelial NRK52E cells. Thus, the inflammatory activation of LPS and TNF-alpha is GSK-3-dependent. Notably, treating mice with GSK-3 inhibitor showed a decrease in LPS-induced renal cell apoptosis in vivo. We further demonstrated that TNF-alpha but not LPS, caused cytotoxicity in NRK52E cells time- and dose-dependently. However, inhibiting GSK-3 slightly decreased TNF-alpha-induced cell apoptosis. Taken together, these results suggest that inhibiting GSK-3 confers anti-inflammation and anti-apoptosis reactions to prevent septic ARF mainly by down-regulating LPS-induced TNF-alpha.

Contents
Abstract in Chinese II
Abstract in English III
Acknowledgement IV
Abbreviations V
Contents VII
List of Figures XI
Chapter I Introduction 1
A Sepsis and Epidemiology of Septic Acute Renal Failure (ARF) 1
B Hemodynamic Pathogenesis of Septic ARF 1
C Nonhemodynamic Pathogenesis of Septic ARF 2
D Relationship between TNF-, Apoptosis, and Septic ARF 3
E Glycogen Synthase Kinase-3 (GSK-3) in Inflammation and Apoptosis 3
F GSK-3 as a Target for Treating Inflammation-Associated Disease 5
Chapter II Study Objective and Specific Aims 7
Objective 7
Specific Aims 7
Chapter III Materials and Methods 9
A Animal Treatment 9
B Histology 9
C Serological Examination 9
D Enzyme-linked Immunosorbent Assay (ELISA) 9
E Cell Culture 10
F Immunostaining 10
G Western Blot 10
H Apoptosis Assay 11
I Cytotoxicity and Viability assay 11
J Statistics 12
Chapter IV Results 13
A LPS Caused Nephrotoxicity Following Systemic Inflammation and Renal Cell Apoptosis 13
B Inhibiting GSK-3 Reduced Mortality and Nephrotoxicity in Endotoxemia-treated C3H/HeN Mice 13
C Inhibiting GSK-3 Suppressed LPS-induced Inflammation In Vivo and In Vitro 14
D Inhibiting GSK-3 Blocked LPS-induced NF-B Nuclear Translocation 15
E Inhibiting GSK-3 Reduced TNF--induced iNOS Expression 15
F Inhibiting GSK-3 Attenuated Renal Cell Apoptosis in LPS-treated Mice But Not in TNF--treated Renal Epithelial Cells 15
Chapter V Discussion 17
Chapter VI Conclusion 22
References 23
Figures and Figure Legends 32
Appendix 45
A Materials 45
A-1 Chemicals 45
A-2 Antibodies and Recombinant Proteins 47
A-3 Consumables 48
A-4 Apparatus 48
B Methods 50
B-1 Animal Experiment 50
B-1.1 Reagents 50
B-1.2 Isolation and treatment of peritoneal macrophages 50
B-1.3 Sacrifice procedures 50
B-2 Animal Survival 51
B-3 Histology 51
B-3.1 Reagents 51
B-3.2 Fixation, dehydration, and embedding 51
B-3.3 Deparaffinization 52
B-3.4 Haematoxylin and Eosin (H&E) Staining 52
B-3.5 Terminal Deoxynucleotidyl Transferase (TdT)-mediated dUTP-Biotin Nick-End Labeling (TUNEL) 52
B-4 Enzyme-linked Immunosorbent Assay (ELISA) 53
B-5 Griess’s Reaction 53
B-6 Protein Concentration Determination 53
B-7 Cell Culture 54
B-7.1 Cell Culture Medium 54
B-7.2 Cell Passage 54
B-7.3 Cell Freeze 54
B-7.4 Cell Defreeze 55
B-8 Immunocytochemistry 55
B-9 Western Blot 55
B-9.1 Lysis buffer 55
B-9.2 5X loading dye and TBS-T 55
B-9.3 Running gel preparation 56
B-9.4 Stacking gel preparation 56
B-9.5 Cell lysate preparation 56
B-9.6 SDS-PAGE 57
B-10 Cell Death and Viability Assay 57
B-10.1 Cytotoxicity detection kit (LDH assay) 57
B-10.2 Cell counting kit-8 (CCK-8 assay) 57
B-10.3 PI staining 57
CURRICULUM VITAE 58

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