臺灣博碩士論文加值系統

大多數的腎臟疾病會攻擊腎元。這種損傷可能使腎臟無法清除廢物，例如急性腎損傷。急性腎損傷存活者中慢性腎臟病的進展通常發生在最初的急性腎損傷的數個月後。有很多流行病學證明高血壓和增加心血管發病率和死亡率都與慢性腎臟病相關聯。位於腦幹背側的孤立束核是由動脈和心肺壓力感受器的傳入纖維產生的第一中樞突觸的部位，被發現在中樞神經系統中是一個重要的血壓調控中心。近期研究發現，第一型血紅素氧化酶可以抵抗組織受損，包括急性腎損傷。因此，首先我們調查第一型血紅素氧化酶在急性腎損傷中參與的細胞保護作用可能的信號通路；並進一步利用5/6腎切除大鼠創建慢性腎臟病模型來研究孤立束核參與的分子機制是否導致慢性腎臟病誘發的高血壓，並進一步發展成第4型心腎症候群。我們研究發現，高鐵血紅素預處理顯著改善腎功能和再灌注後的腎小管損傷，並在72小時增強腎小管恢復。給予高鐵血紅素誘導小鼠腎中的第一型血紅素氧化酶活化和ERK1 / 2磷酸化，以及通過鋅原卟啉IX（ZnPP）阻斷了ERK1 / 2和第一型血紅素氧化酶激活。蛋白質印跡和免疫熒光研究進一步證實了高鐵血紅素預處理刺激第一型血紅素氧化酶誘導腎小管增殖，並且PD98059治療減弱了這種效應。我們的研究探討如何減少慢性腎臟病的惡化。結果發現腎神經去除通過降低交感神經活動改善慢性腎臟病的血壓，並顯著恢復的壓力感受器反應。除此之外，我們利用蛋白質體學和生物信息分析來確定孤立束核中什麼分子機制導致慢性腎臟病誘發高血壓。研究發現，γ-氨基丁酸B受體的表達在慢性腎臟病的孤束核中增加；γ-氨基丁酸在腦脊液中減少，在血清中升高。然而，腎神經去除恢復了慢性腎臟病之孤束核的谷氨酸脫羧酶活性，類似於中樞治療巴氯芬和口服給予加巴噴丁，所觀察到的降血壓反應。綜合上述，我們證明第一型血紅素氧化酶預處理在缺血性急性腎損傷的初始階段，是透過活化ERK1 / 2的增殖反應促進腎小管恢復，而不是透過減少腎損傷。 在急性腎損傷發展成慢性腎臟病的情況下，腎神經去除可以改善γ-氨基丁酸功能來降低血壓，並進一步降低慢性腎臟病的惡化。

Most kidney diseases attack the nephrons. This damage may leave kidneys unable to remove wastes such as acute kidney injury (AKI). The progression of chronic kidney disease (CKD) in these AKI survivors typically occurs months after the initial AKI insult. There is much epidemiological demonstrated that hypertension and increased cardiovascular morbidity and mortality all linking with CKD. The nucleus tractus solitarii (NTS) is the site where afferent fibers arising from the arterial and cardiopulmonary baroreceptors make the first central synapses. Recent studies indicate that Heme oxygenase (HO)-1 can resist against tissues damage, including kidney injury. Therefore, we first investigated the possible signaling pathways that are involved in the cytoprotective effects of HO-1 in AKI, and next utilized the CKD model to investigate that the molecular mechanisms were involved in the NTS lead CKD-induced hypertension and further the development of cardiorenal syndrome type 4 by 5/6 nephrectomized rats. Our study showed that hemin pretreatment significantly ameliorated renal function and tubular damage after reperfusion and enhanced tubular recovery at 72 hours. Hemin administration induced HO-1 activation and ERK1/2 phosphorylation in mouse kidneys and the blockade of ERK1/2 and HO-1 activation by zinc-protoporphyrin IX (ZnPP). Western blot and immunofluorescence studies further demonstrated that hemin pretreatment stimulated an HO-1-induced tubular proliferation, and PD98059 treatment attenuated this effect. Next, our study investigated how to reduce the deterioration of CKD. We discovered that renal denervation (RD) improved the blood pressure (BP) by lowering sympathetic nerve activity (SNA) and markedly recovered the baroreflex response in CKD. In addition, we utilized proteomics and bioinformatics analysis to determine what the molecular mechanisms lead to CKD-induced hypertension in the NTS. We investigated that GABAB receptor expression was increased in the NTS of CKD; the central GABA levels were reduced in the CSF, and the peripheral GABA levels were increased in the Serum. However, RD recovered glutamic acid decarboxylase activity in the NTS in CKD, similar to that observed with central treatment with baclofen, and the systemic administration of gabapentin reduced the BP. Taken together, we demonstrated that HO-1 preconditioning improves tubular recovery through a proliferative response induced by activated ERK1/2, rather than through reducing kidney injury in the initial phase of ischemic AKI. In case AKI progresses to CKD, RD can improve GABA function to decrease BP, and further reduce the deterioration of CKD.

Contents ..........................................I
English Abstract ………………………………………………………………..........V
Chinese Abstract ……………………………………………………...........VII
List of Abbreviations ……………………………………………………………......IX
List of Tables …………………………………………………………………...........XI
List of Figures ………………………………………………..…………………........XII
Introduction ……………………………………………………………………............1
Kidney and kidney injury …………………………………………….........1
Renoprotective effects of HO-1 in kidney injury …….2
HO-1 and signal transduction ………………………………….……………..…3
Acute kidney injury to chronic kidney disease …….….4
Chronic renocardiac syndrome in CKD ………………….….……………5
Renal denervation blood pressure control in CKD …….5
Renal afferent nerves converge into the nucleus tractus solitarii ………..6
Hypothesis and Specific aims ………………………………………..…..……7
Materials and Methods ……..……………………………………………..…....…8
Animal care and experiments ……………………………………………..…...8
Ischemia-reperfusion injury procedures ………………………………8
5/6 nephrectomy procedures ………………………………………………….....9
Renal ischemia-reperfusion model ………………………………...…..10
Histopathological examination ………………………………………...…..11
Western Blot Analysis ………………………………………………………........12
Immunohistochemistry analysis …………………………………………..…..13
EdU labeling in the mouse model ………………………………………..….13
Echocardiography analysis ………………………………………………..…....13
General characteristics of blood …………………………………………….14
Blood pressure measurement ………………………………………….…......14
Sympathetic nerve recordings and the baroreflex response analysis ………………………………………………………………….…........................15
Proteomics analysis using two-dimensional electrophoresis ...................................................15
In-gel digestion ……………………………………………………….….........……16
LC-MS/MS analysis …………………………………………………………...........17
Mass data analysis ……………………………………………...……….……......17
Real-Time PCR analysis …………………………………………………..…......18
Assay of cerebrospinal fluid and serum GABA and glutamate levels ………………………………………………………………………..….....................19
GAD activity assay …………………..………………………………………........19
Statistical analysis ……………………………………….…………….……......19
Result …………………………………………………………………..……..............…21
Hemin preconditioning could protect kidney injury from renal IRI ………………………………………………………………………….….....................21
Hemin preconditioning induces HO-1 expression in the kidney cortex …..…………………………………………………………………..….......................22
HO-1 induces ERK1/2 activation in the kidney cortex …………….…..............................................…...22
HO-1 enhances early kidney function recovery by activating ERK 1/2 ..……………………………………………………………….…………….....................22
HO-1 enhances kidney function recovery by promoting early renal tubular epithelium proliferation through ERK1/2 activation …………...…............................................…..…..23
CKD induced hypertension and cardiovascular disorders by 5/6 nephrectomy ……………………………………………………………….........................….24
RD reduces the BP by improving the SNA, and restores the baroreflex response in CKD ………………………………………………………….…...........24
RD reverses the increased GABAB receptor expression and normalizes the GABA levels in CKD …………………………………………………..…….............…26
RD improves GAD activity and reverses the GABA dysfunction in CKD with hypertension ……………………………………………………………..…............27
RD improves chronic renocardiac syndrome (CRS type 4) in CKD …….28
Discussion ……………………………………………………………………..............30
The reason of Ho-1 cytoprotective properties are recovery, not protection ………………………………………………………..……..…….....................…30
HO-1 activates ERK1/2 and then leads to the protective effect in AKI …………………………………………………………………………….....................…31
ERK1/2 activation leads to tubular epithelial cell proliferation ………...............................................…33
AKI recovery may lead to the development of CKD and how to improve the prognosis of CKD ……………………………………………...…………….........33
RD through GABA system reduces sympathetic hyperactivity, and impaired baroreflex responses lead to the hypotensive response ……………….............................................34
Control central nervous system by GABA system ……………….........................................……….35
RD treats psychotic disorders from clinical perspective …………….............................................…36
The advantages and disadvantages of RD ………………………..…................................................……37
Conclusion ……………………………………………………………..….................................................…39
Future Perspectives …………………...……………………………….….......40
References ……………………………………………………………...….........…42
Tables …………………………………………………..……………………...............53
Figures and Figure Legends ……………..……………………………….....58
Appendices ………………………………………………………….……..…..….........81
Publications …………………………………………………………..….……..........99

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