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系統識別號 U0026-0204201415124700
論文名稱(中文) 腦內Klotho在神經保護與維持心血管感壓反射中所扮演的角色
論文名稱(英文) Role of cerebral klotho in neuronal protection and the maintenance of the cardiovascular baroreflex
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 陳立仁
研究生(英文) Li-Jen Chen
學號 S58961361
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-鄭瑞棠
召集委員-唐一清
口試委員-張南山
口試委員-蘇俊魁
口試委員-許惠恒
口試委員-吳達仁
中文關鍵字 Klotho  紅血球生成素受體  GATA1  STAT5  Jak2  感壓反射  自發性高血壓大鼠  腦室內輸注  格列酮  鏈脲佐菌素誘發糖尿病大鼠 
英文關鍵字 Klotho  EpoR  GATA1  STAT5  Jak2  Baroreflex  Klotho shRNA  SHR  ICV infusion  TZD  STZ rat 
學科別分類
中文摘要 研究顯示,紅血球生成素受體(EpoR)會在腦中表現且已被證實具有保護神經的功能。先前的研究顯示,Klotho可透過增加EpoR的表現,促進其對腎細胞的保護效應。在本研究的第一個部份,我們假設Klotho能增加神經細胞EpoR的表現,從而促進促紅血球生成素(Epo)所引致的神經細胞保護效應。我們的研究結果顯示,在H19-7細胞中, Klotho可以增加EpoR的蛋白和mRNA的表現。Klotho細胞也增加了紅血球生成素所誘導的Jak2的和Stat5磷酸化,並且在H19 -7細胞降低過氧化氫造成的細胞毒性。透過siRNA沉默化EpoR的表現也抵消了Klotho對細胞的保護作用。最後, 透過siRNA沉默化GATA1也降低了Klotho 所誘導的EpoR蛋白質,mRNA和啟動子活性。
第一部份的結果證實Klotho具有保護神經細胞的作用,Klotho蛋白質是由脈絡叢產生,作為在中樞神經系統中的漿液性因子,沉默化腦中的Klotho會導致寒冷所誘發的升血壓反應更加劇烈。因此,本研究的第二個部分旨在探討腦中Klotho與感壓反射之間的關聯。結果顯示,自發性高血壓大鼠在腦室注入Klotho重組蛋白(rKL)後,感壓反射顯著地恢復。相反地,在正常大鼠腦室注入Klotho的shRNA可觀察到感壓反射顯著地變差。此外,連續以藥物升降血壓誘發感壓反射,會導致的Klotho在延腦的表現量增加。接著,將此發現進一步應用治療糖尿病所引致的感壓反射不敏感上。先前的研究證實,PPAR為Klotho調控因子,而臨床上常用於治療糖尿病的胰島素增敏劑格列酮(TZDs)類藥物即為PPAR的刺激劑。結果顯示,腦室連續7天注入重組的Klotho 或連續7天每日口服10mg/kg口服TZD均可令鏈脲佐菌素( STZ )誘導的糖尿病大鼠心跳速率(HR)或平均動脈血壓(MAP)趨近正常大鼠且感壓反射也有顯著的恢復。
綜合以上結果,在神經元細胞中, Klotho通過GATA1轉錄因子增加EpoR啟動子活性以及蛋白質、mRNA表現,進而增進對於神經細胞的保護作用。沉默大腦中的Klotho表現可降低感壓反射。恢復SHR大鼠和糖尿病大鼠大腦Klotho表現可以回復受損的感壓反射。因此,腦內Klotho在神經保護與維持心血管感壓反射中扮演重要的角色,口服投予TZD提高的腦中Klotho的表現,對於恢復糖尿病所引致的感壓反射低下有顯著的效果。
英文摘要 The Epo (Erythropoietin) receptor (EpoR) is expressed in the brain and has been shown to be neuroprotective against brain damage in animal models. Previous reports have indicated that EpoR and its activity are downstream effectors of Klotho enabling it to function as a cytoprotective protein in the kidney. In the first part of the study, we propose that Klotho can stimulate the expression of EpoR on cultured neuronal cells and can thus contribute to Epo-mediated protection. In the H19-7 cells, Klotho increased the expression of the EpoR protein and transcript. Klotho also augmented the Epo-triggered phosphorylation of Jak2 and Stat5, and protected H19-7 cells from hydrogen peroxide cytotoxicity. The silencing of EpoR abolished the protective effect of Klotho against peroxide-induced cytotoxicity. Finally, the silencing of GATA1 diminished the Klotho-induced expression of EpoR.
The neuronal protective effects of klotho were demonstrated in the first part of this study. The Klotho protein is produced by the choroid plexus as a humoral factor in the central nervous system. The silencing of Klotho in the brain has been reported to enhance the cold-induced elevation of blood pressure. Thus, we investigated the role of Klotho in the maintenance of the baroreflex sensitivity (BRS) in the second part of this study. We found that baroreflex sensitivity is decreased after the silencing of Klotho expression by the injection klotho shRNA to the brain in Wistar Kyoto (WKY) rats. Additionally, the modulation of the blood pressure for one week altered the cardiovascular homeostasis and resulted in an increased expression of Klotho in the medulla oblongata. Moreover, the baroreflex sensitivity was restored in spontaneously hypertensive rats (SHRs) that received recombinant Klotho through intracerebroventricular (ICV) infusion. To apply these findings, we attempted to develop a new therapeutic strategy for the treatment of diabetes-induced baroreflex insensitivity. The expression of Klotho is regulated by PPAR. Rosiglitazone is a clinically used thiazolidinedione (TZD) and is a PPAR agonist. Finally, the cerebral infusion of recombinant Klotho for 7 days or oral administration of TZD (10 mg/kg for 7 days) reversed both the HR and the mean blood pressure (MBP) to control values and normalized the BRS in streptozocin-induced diabetic rats.
In conclusion, Klotho increased EpoR expression in neuronal cells through GATA1, thereby enabling EpoR to function as a cytoprotective protein against oxidative injury. Silencing the expression of Klotho in the brain may decrease the baroreflex responses. The subsequent recovery of Klotho expression in the brain may restore the BRS in SHR and diabetic rats. Thus, cerebral Klotho is important in the neuronal protection and maintenance of the cardiovascular baroreflex. Additionally, TZD can reverse the reduced BRS through higher cerebral Klotho in diabetic disorders.
論文目次 Abstract……………………………………………………………………………………...i
中文摘要…………………………………………………………………………………...iii
誌謝…………………………………………………………………………………………v
Contents………………………………………………………………………………….....vi
Tables…………………………………………….…………………………………………x
Figures……………………………………………………………………………………...xi
Abbreviations……………………………………………………………………………..xiii
Chapter 1 Introduction…………………....…………………………………...……….……1
1.1 A brief review of Klotho……………......…………..…………………………………..2
1.2 The role of EpoR signaling in cytoprotection………………………..…………………3
1.3 Klotho expression is associated with cardiovascular diseases…..……………………...4
1.4 Baroreflex……………………………………………………………………………….5
1.5 Regulation of the baroreflex by peptides in the cerebrospinal fluid (CSF).…………….6
1.6 Baroreflex and diabetes…………………………………………………………………7
1.7 PPAR is an upstream regulator of Klotho…...………………………………………...8
1.8 Aims………………………………………………………………………………….....9
Chapter 2 Materials and methods……………………………………………….…………10
2.1 Animals………………………………………………………………………………..11
2.2 Cell culture…………………………………………………………………………….11
2.3 Streptozotocin (STZ)-induced type 1-like diabetic rats...……………………………..12
2.4 Drug administration of the STZ rats…………………………………...………………13
2.5 Western blotting analysis……………………………………………………………...13
2.6 RNA interference……………………………………………………………………...14
2.7 Real-time reverse transcription-polymerase chain reaction…………………………...14
2.8 EpoR gene transfection and activity assay…………………………………………….15
2.9 Assessment of H2O2-induced cytotoxicity in H19-7 cells………………………….…15
2.10 Intracerebroventricular (ICV) injections..……………………………………………16
2.11 Phenylephrine (PE)-induced hypertension and sodium nitroprusside (SNP)-induced hypotension……………………………………………………………………….…..17
2.12 Blood pressure and heart rate recording………………...……………………………17
2.13 Baroreflex challenge and evaluation…………………………………………………18
2.14 Statistical Analysis…………………………………………………………………...19
Chapter 3 Results…………………………………………………………………………..20
3.1 Klotho increases EpoR protein and mRNA expression in H19-7 neuronal cells……...21
3.2 Klotho enhance the activation of downstream EpoR effectors………………………..21
3.3 Klotho protects H19-7 cells from H2O2-induced cytotoxicity via EpoR……………..22
3.4 The effects of GATA1 siRNA on the Klotho induced expression of EpoR in H19-7 cells…………………………………………………………………………………….23
3.5 The expression of the Klotho protein in the medulla oblongata………………………23
3.6 ICV infusion of recombinant klotho restored the baroreflex response in spontaneous hypertensive rats (SHRs)……………………….……………………………………...24
3.7 The baroreflex response is attenuated in rats after the silencing of klotho expression in the medulla oblongata…………………………………………………..……………..24
3.8 Increase of klotho expression by PE-induced hypertension and SNP-induced hypotension……………………………………………………………………………25
3.9 Klotho expression in the medulla oblongata of streptozotoxin-induced diabetic rats (STZ-diabetic rats)…………………………………………………………………….25
3.10 ICV infusion of recombinant Klotho restored the baroreflex responses in STZ-diabetic rats…………………………………………………………………………………..…26
3.11 The effect of rosiglitazone (TZD) on the expression of Klotho in medulla oblongata of STZ rats………………………………………………………………………………..26
3.12 The baroreflex response is restored in STZ rats after oral administration of TZD................................................................................................................................26
Chapter 4 Discussion……………………………………………………………………....28
Chapter 5 Conclusion.………………………………………………………….………….39
References…………………………………………………………………………………41
Figure legends……………………………………………………………………………..62
Appendix…………………………………………………………………………………105
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