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研究生:羅兆盛
研究生(外文):Chao-Sheng Lo
論文名稱:腎臟腎小管心房利鈉胜肽之功能與調節
論文名稱(外文):Function and Regulation of Renal Tubular ANP
指導教授:辛錫璋辛錫璋引用關係
指導教授(外文):Shyi-Jang Shin
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:169
中文關鍵詞:心房利鈉胜肽近端腎小管細胞乙型轉型因子腎素-血管張力素系統小干擾因子
外文關鍵詞:ANPProximal tubular celTGF-beta1Renin-angiotensin systemRASsmall interfering RNA
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中文摘要
糖尿病病人常合併有腎臟病變現象。糖尿病腎病變的主要病理特徵,大多會有腎絲球過度增生及腎小管肥大的現象。高血糖通常是造成糖尿病血管病變,腎臟病變,及視網膜病變的主要因子。在許多疾病下,腎臟合成心房利鈉胜肽(ANP)表現會增加,例如:糖尿病。然而,腎臟合成ANP產生局部保護的功能,到目前為止也尚不清楚。高血糖對細胞造成的傷害是否可以經由ANP而減弱,目前機制尚未明確。
本論文主要探討高糖刺激下,ANP在近端腎小管細胞中的角色功能與調控機轉。主要涵蓋了三個研究方向:第一部份,探討ANP在高糖刺激近端腎小管細胞中之功能。第二部份,研究內源性ANP在近端腎小管細胞中扮演之角色。第三部份,探討內源性ANP在高糖刺激近端腎小管細胞中調控機轉。

第一部分:ANP在近端腎小管細胞經高糖活化TGF-β1 /Smad/ collagen 途徑之探討
在糖尿病大白鼠疾病模式下,特別是在近端腎小管,ANP的表現增加。所以可以合理的假設腎臟合成的ANP具有調節,經高血糖造成的細胞傷害。
利用外加ANP的方式,探討ANP在高糖刺激近端腎小管細胞中,是否具有保護現象。高糖刺激近端腎小管細胞,TGF-β1與collagen type I表現增加。外加10-6M ANP後,可以減弱高糖刺激細胞後,TGF-β1與collagen type I的表現。當給予LY83583 (cGMP抑制劑)抑制ANP訊息傳遞後,發現會減弱ANP的抑制能力。另外也發現,高糖刺激近端腎小管後,p-Smad 2/3表現量增加。外加ANP,也具有減弱p-Smad 2/3表現量。

第二部分:內源性ANP在近端腎小管細胞中角色之探討
近端腎小管中,內源性ANP在局部功能的研究,目前尚不明確。近端腎小管經高糖刺激後,產生許多促進腎臟纖維化(例如:TGF-β1)與發炎因子(例如:NF-κB)的表現。利用轉殖ANP與傳送siRNA技術,探討內源性ANP在近端腎小管中,是否具有保護腎臟,避免高血糖的傷害。
研究發現,利用轉殖ANP,大量表現ANP及小干擾片段(siRNA),抑制ANP表現。ANP在近端腎小管細胞中,具有減弱高糖刺激下產生TGF-β1與NF-κB。另外也發現,ANP在近端腎小管細胞中,抑制NF-κB表現,可能經由活化細胞內的IκB-α蛋白途徑。

第三部分: 在近端腎小管細胞中高糖活化ANP生合成經angiotensinogen途徑之探討
糖尿病腎病變中,腎素-血管張力素系統 (renin-angiotensin system; RAS)扮演一重要的角色。近端腎小管細胞在高糖或是ANG II培養下,會產生細胞肥大及細胞外間質增生的現象。在高糖刺激近端腎小管細胞後,ANP在細胞內表現也增加。所以,可以合理的假設RAS應該具有調節腎臟合成ANP的功能。
這部分利用高糖刺激近端腎小管細胞,發現細胞內angiotensinogen (ANG)與ANP mRNA表現增加,培養液內ANG II的蛋白含量也增加。外加10-6M ANG II,可以直接刺激細胞內ANP的生合成增加。細胞在高糖刺激下,分別在培養液中外加Losartan與PD123319,抑制ANG II訊息,會減少細胞內ANP的表現。利用siRNA抑制ANG的表現,發現近端腎小管細胞經高糖刺激後,會減少細胞內ANP的表現。另外也發現,利用siRNA抑制ANP的表現,會增加細胞經高糖刺激後ANG II的表現。研究證實,高糖會刺激細胞ANG的生合成,培養液中ANG II表現增加,並且經由受體活化下游訊息,調控細胞內ANP的生合成。另一方面,高糖活化細胞內ANP表現,具有抑制高糖刺激細胞ANG II的功能。
總合上述研究結果,利用近端腎小管細胞探討,腎臟合成ANP的局部功能與調控,能直接的解釋近端腎小管細胞,在高糖刺激下,內源性ANP的角色功能與作用機轉。
英文摘要
Kidney disease is one of the complications of diabetes. The pathophysiologic changes in diabetic nephropathy including mesangial cells proliferation and tubular cells hypertrophy. Hyperglycemia is the initial trigger of vascular, renal and retinal cells damage associated with diabetes. Renal ANP synthesis has been found to be significantly increased in several disorders, eg. diabetes. ANP synthesized from the kidney produces local function has never been elucidated. Hyperglycemia-induced cell damage can also be modulated by ANP is still unclear.
This dissertation concerning the role and function of renal ANP synthesis in high glucose stimulated in renal tubular epithelial cells. In this study, we have mainly contained three research directions. First, we investigated the function of ANP by high glucose-stimulated in renal tubular epithelial cells. Second, we investigated the role of endogenous ANP in renal tubular epithelial cells. Third, we investigated the regulation of endogenous ANP by glucose-stimulated in renal tubular epithelial cells.
I. The study of ANP on high glucose-activated transforming growth factor-beta1 (TGF-β1), Smad and collagen synthesis in renal proximal tubular cells.
In diabetic rats, ANP synthesis has been found to be significantly increased, particularly in the proximal tubules. It is reasonable to hypothesize that renal ANP synthesis might directly modulate hyperglycemia-induced injure in this cells.
First, we concerned about cytoprotective action in renal tubular cells by addition of ANP. High glucose significantly increased TGF-β1 and collagen type I expression in renal proximal tubular cells. The addition of ANP significantly attenuated high glucose-enhanced TGF-β1 and collagen type I. LY83583 blocked the influence of ANP on high glucose-activated TGF-β1 and collagen synthesis. In addition, ANP significantly attenuated high glucose-enhanced p-Smad 2/3 ratio.
II. The role of endogenous ANP in renal proximal tubular cells.
It is still unclear on endogenous ANP exerts local function in renal proximal tubular cells. Hyperglycemia activates numerous profibrotic and pro-inflammatory mediators, such as TGF-β1 and NF-κB in renal proximal tubular cells. We investigated whether endogenous ANP could modulate high glucose-stimulated TGF-β1 and collagen type I in renal proximal tubular cells using transfection of ANP and ANP small interfering RNA (siRNA).
In this study, the transfection of ANP significantly attenuated high glucose-activated TGF-β1 and NF-κB expression. ANP siRNA knocked-down ANP but significantly increased TGF-β1 and NF-κB under high glucose conditions. In addition, IkB-α expression increased in ANP-transfected cells, and in contrast, IkB-α expression decreased in ANP siRNA-transfected cells. These results imply an inhibitory action of ANP on NF-κB inhibition by up-regulation of IkB-α.
III. The study of high glucose induces ANP-synthesis via intrarenal renin-angiotensin system in renal proximal tubular cells
Renin-angiotensin system play an important role in diabetic nephropathy. High glucose or angiotensin II could stimulate cells hypertrophy and extracellular matrix formation in renal tubular cells. Therefore, we investigated whether intrarenal renin-angiotensin system could modulate renal ANP synthesis in high glucose-stimulation in proximal tubular cells.
Proximal tubular cells were stimulated with high glucose to up-regulate ANP and ANG mRNA and ANG II protein level. These effects of high glucose were attenuated by angiotensin II receptor antagonist ( losartan or PD123319). ANG siRNA silenced ANG expression, and down-regulate ANP expression in high glucose stimulation in renal tubular cells. In this study, high glucose can stimulate angiotensinogen and angiotensin II expression. High glucose induces ANP-synthesis via intrarenal renin-angiotensin system in renal proximal tubular cells.
In conclusion, using proximal tubular cells to investigate local action of endogenous ANP can directly explanation for the function and regulation of renal ANP synthesis on high glucose-activated in proximal tubular cells.
目 錄
中文總摘要 ………………………………………………………… 1
英文總摘要 ………………………………………………………… 5
縮寫表 ……………………………………………………………… 8
第一章 緒論………………………………………………………… 9
第二章 心房利鈉胜肽在近端腎小管細胞經高糖活化TGF-β1 /Smad/ collagen 途徑之探討
一、中文摘要…………………………………………………………28
二、 前言…………………………………………………………… 29
三、 材料方法 ………………………………………………………31
四、 結果…………………………………………………………… 38
五、 討論…………………………………………………………… 43
六、 圖表…………………………………………………………… 47
第三章 內源性心房利鈉胜肽在近端腎小管細胞中角色之探討
一、中文摘要…………………………………………………………64
二、 前言…………………………………………………………… 67
三、 材料方法 ………………………………………………………69
四、 結果…………………………………………………………… 80
五、 討論…………………………………………………………… 88
六、 圖表…………………………………………………………… 91
第四章 在近端腎小管細胞中高糖活化ANP生合成經angiotensinogen途徑之探討
一、中文摘要…………………………………………………………113
二、 前言…………………………………………………………… 115
三、 材料方法 ………………………………………………………117
四、 結果…………………………………………………………… 120
五、 討論…………………………………………………………… 123
六、 圖表…………………………………………………………… 125
第五章 總結論……………………………………………………… 135
參考文獻 …………………………………………………………… 141
< 附錄 > 論文與學會發表………………………………………… 157
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